Vascular aging: Molecular mechanisms and potential treatments for vascular rejuvenation

Aging is the main risk factor contributing to vascular dysfunction and the progression of vascular diseases. In this review, we discuss the causes and mechanisms of vascular aging at the tissue and cellular level. We focus on Endothelial Cell (EC) and Smooth Muscle Cell (SMC) aging due to their critical role in mediating the defective vascular phenotype. We elaborate on two categories that contribute to cellular dysfunction: cell extrinsic and intrinsic factors. Extrinsic factors reflect systemic or environmental changes which alter EC and SMC homeostasis compromising vascular function. Intrinsic factors induce EC and SMC transformation resulting in cellular senescence. Replenishing or rejuvenating the aged/dysfunctional vascular cells is critical to the effective repair of the vasculature. As such, this review also elaborates on recent findings which indicate that stem cell and gene therapies may restore the impaired vascular cell function, reverse vascular aging, and prolong lifespan.

[1]  K. Kang,et al.  DNA Methyltransferase Controls Stem Cell Aging by Regulating BMI1 and EZH2 through MicroRNAs , 2011, PloS one.

[2]  Jianmin Wang,et al.  NANOG Reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF‐Dependent Gene Expression , 2017, Stem cells.

[3]  S. Dymarkowski,et al.  Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial , 2006, The Lancet.

[4]  G. Hannon,et al.  A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 , 1993, Nature.

[5]  D. Vassallo,et al.  Toll-Like Receptor 4 Upregulation by Angiotensin II Contributes to Hypertension and Vascular Dysfunction through Reactive Oxygen Species Production , 2014, PloS one.

[6]  T. Littlewood,et al.  Effects of DNA damage in smooth muscle cells in atherosclerosis. , 2015, Circulation research.

[7]  T. Misteli,et al.  Lamin A-Dependent Nuclear Defects in Human Aging , 2006, Science.

[8]  Badrinath Roysam,et al.  A hyperfused mitochondrial state achieved at G1–S regulates cyclin E buildup and entry into S phase , 2009, Proceedings of the National Academy of Sciences.

[9]  Jun Yamashita,et al.  Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors , 2000, Nature.

[10]  Baojie Li,et al.  p53 Deficiency Leads to Compensatory Up-Regulation of p16INK4a , 2009, Molecular Cancer Research.

[11]  R. Weindruch,et al.  High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys , 1995, Mechanisms of Ageing and Development.

[12]  M. Simionescu,et al.  AP-1–Dependent Transcriptional Regulation of NADPH Oxidase in Human Aortic Smooth Muscle Cells: Role of p22phox Subunit , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[13]  T. Littlewood,et al.  Chronic Apoptosis of Vascular Smooth Muscle Cells Accelerates Atherosclerosis and Promotes Calcification and Medial Degeneration , 2008, Circulation research.

[14]  J. Maier,et al.  Senescence-dependent regulation of type 1 plasminogen activator inhibitor in human vascular endothelial cells. , 1995, Experimental cell research.

[15]  T. Littlewood,et al.  Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis , 2006, Nature Medicine.

[16]  Jinqiu Zhang,et al.  A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. , 2011, Cell stem cell.

[17]  I. Weissman,et al.  Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth , 2008, Proceedings of the National Academy of Sciences.

[18]  S. Both,et al.  Bone tissue-engineered implants using human bone marrow stromal cells: effect of culture conditions and donor age. , 2002, Tissue engineering.

[19]  N. Nikolsky,et al.  Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells , 2014, Aging.

[20]  A. Malik,et al.  NANOG induction of fetal liver kinase-1 (FLK1) transcription regulates endothelial cell proliferation and angiogenesis. , 2011, Blood.

[21]  J. Yatabe,et al.  Salt sensitivity is associated with insulin resistance, sympathetic overactivity, and decreased suppression of circulating renin activity in lean patients with essential hypertension. , 2010, The American journal of clinical nutrition.

[22]  M. Bennett,et al.  Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. , 1998, Circulation research.

[23]  Qilong Wang,et al.  Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission , 2016, Diabetes.

[24]  Laura C. Greaves,et al.  Chronic inflammation induces telomere dysfunction and accelerates ageing in mice , 2014, Nature Communications.

[25]  M. Joyner,et al.  Aging decreases expression and activity of glutathione peroxidase-1 in human endothelial progenitor cells. , 2009, Microvascular research.

[26]  A. Brandl,et al.  Oxidative stress induces senescence in human mesenchymal stem cells. , 2011, Experimental cell research.

[27]  S. Hung,et al.  Knockdown of p21Cip1/Waf1 enhances proliferation, the expression of stemness markers, and osteogenic potential in human mesenchymal stem cells , 2011, Aging cell.

[28]  T. Jensen,et al.  Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells , 2002, Nature Biotechnology.

[29]  S. Tarantini,et al.  Aging Exacerbates Pressure-Induced Mitochondrial Oxidative Stress in Mouse Cerebral Arteries. , 2015, The journals of gerontology. Series A, Biological sciences and medical sciences.

[30]  T. Spector,et al.  Common variants near TERC are associated with mean telomere length , 2010, Nature Genetics.

[31]  C. Bearzi,et al.  Identification of a coronary vascular progenitor cell in the human heart , 2009, Proceedings of the National Academy of Sciences.

[32]  Simon C. F. Sheng,et al.  Milk Fat Globule Protein Epidermal Growth Factor-8: A Pivotal Relay Element Within the Angiotensin II and Monocyte Chemoattractant Protein-1 Signaling Cascade Mediating Vascular Smooth Muscle Cells Invasion , 2009, Circulation research.

[33]  Albert Hofman,et al.  Nucleotide Excision DNA Repair Is Associated With Age-Related Vascular Dysfunction , 2012, Circulation.

[34]  Z. Ungvari,et al.  Oxidative stress and accelerated vascular aging: implications for cigarette smoking. , 2009, Frontiers in bioscience.

[35]  R. Hebbel,et al.  Origins of circulating endothelial cells and endothelial outgrowth from blood. , 2000, The Journal of clinical investigation.

[36]  Hiroshi Iwata,et al.  Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease. , 2016, Cell stem cell.

[37]  M. Makuuchi,et al.  Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis , 2002, Nature Medicine.

[38]  D. Stewart,et al.  Rescue of Monocrotaline-Induced Pulmonary Arterial Hypertension Using Bone Marrow–Derived Endothelial-Like Progenitor Cells: Efficacy of Combined Cell and eNOS Gene Therapy in Established Disease , 2005, Circulation research.

[39]  L. Barbeito,et al.  Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis. , 2014, Free radical biology & medicine.

[40]  Christian Clausen,et al.  Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. , 2003, Bone.

[41]  A. Rusiñol,et al.  Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors , 2006, Journal of Cell Science.

[42]  S. Segal,et al.  Small Vessels – Big Problems : Novel Insights into Microvascular Mechanisms of Diseases Advanced age decreases local calcium signaling in endothelium of mouse mesenteric arteries in vivo , 2016 .

[43]  Pascal J. Goldschmidt-Clermont,et al.  Aging, Progenitor Cell Exhaustion, and Atherosclerosis , 2003, Circulation.

[44]  K. Siddle,et al.  Defect in Insulin-Like Growth Factor-1 Survival Mechanism in Atherosclerotic Plaque-Derived Vascular Smooth Muscle Cells Is Mediated by Reduced Surface Binding and Signaling , 2001, Circulation research.

[45]  E. Stadtman,et al.  Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients , 2010, Mechanisms of Ageing and Development.

[46]  L. Niklason,et al.  Relevance and safety of telomerase for human tissue engineering. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Qikai Xu,et al.  The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4 , 2015, Science.

[48]  N. Markandu,et al.  Angiotensin II suppression is a major factor permitting excretion of an acute sodium load in humans. , 1994, The American journal of physiology.

[49]  Richard A. Kronmal,et al.  Distribution of Coronary Artery Calcium by Race, Gender, and Age: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) , 2005, Circulation.

[50]  N. Fineberg,et al.  Definitions and Characteristics of Sodium Sensitivity and Blood Pressure Resistance , 1986, Hypertension.

[51]  Yuqi Liu,et al.  Maternally Inherited Essential Hypertension Is Associated With the Novel 4263A>G Mutation in the Mitochondrial tRNAIle Gene in a Large Han Chinese Family , 2011, Circulation research.

[52]  J. Skepper,et al.  Prelamin A Acts to Accelerate Smooth Muscle Cell Senescence and Is a Novel Biomarker of Human Vascular Aging , 2010, Circulation.

[53]  Hiroshi Takahashi,et al.  Enhanced inhibition of hepatitis B virus production by asialoglycoprotein receptor-directed interferon , 1999, Nature Medicine.

[54]  T. Matsuo,et al.  Telomere Shortening in Human Coronary Artery Diseases , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[55]  M. Prins,et al.  Carotid Stiffness in Young Adults: A Life-Course Analysis of its Early Determinants The Amsterdam Growth and Health Longitudinal Study , 2012, Hypertension.

[56]  P Lindau,et al.  Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip , 2011, Nature.

[57]  S. Andreadis,et al.  Molecular and functional effects of organismal ageing on smooth muscle cells derived from bone marrow mesenchymal stem cells. , 2010, Cardiovascular research.

[58]  Qingbo Xu,et al.  Endothelial Replacement and Angiogenesis in Arteriosclerotic Lesions of Allografts Are Contributed by Circulating Progenitor Cells , 2003 .

[59]  H. Oxlund,et al.  Changes in biomechanical properties, composition of collagen and elastin, and advanced glycation endproducts of the rat aorta in relation to age. , 1996, Atherosclerosis.

[60]  Laura S. Shankman,et al.  Correction: Corrigendum: KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis , 2015, Nature Medicine.

[61]  Jianmin Zhang,et al.  p16INK4a modulates p53 in primary human mammary epithelial cells. , 2006, Cancer research.

[62]  C. Harley,et al.  Telomere length and replicative aging in human vascular tissues. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[63]  R. Hamdy,et al.  Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells. , 1998, Biochimica et biophysica acta.

[64]  Joel S Greenberger,et al.  Age‐related intrinsic changes in human bone‐marrow‐derived mesenchymal stem cells and their differentiation to osteoblasts , 2008, Aging cell.

[65]  T. Lüscher,et al.  Enhanced Peroxynitrite Formation Is Associated with Vascular Aging , 2000, The Journal of experimental medicine.

[66]  C. Lau,et al.  Prevalence, Awareness, Treatment, and Control of Hypertension Among United States Adults 1999–2004 , 2007, Hypertension.

[67]  Linda J. Kuo,et al.  γ-H2AX - A Novel Biomarker for DNA Double-strand Breaks , 2008 .

[68]  E. Kirkness,et al.  Somatic coding mutations in human induced pluripotent stem cells , 2011, Nature.

[69]  Douglas R Seals,et al.  Aerobic exercise reverses arterial inflammation with aging in mice. , 2011, American journal of physiology. Heart and circulatory physiology.

[70]  H. Saya,et al.  Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence , 2006, Nature Cell Biology.

[71]  F. Byfield,et al.  Endothelial actin and cell stiffness is modulated by substrate stiffness in 2D and 3D. , 2009, Journal of biomechanics.

[72]  W. Zhou,et al.  Mutation of the protein kinase A phosphorylation site influences the anti-proliferative activity of mitofusin 2. , 2010, Atherosclerosis.

[73]  S. Masetti,et al.  Evidence for DNA damage in patients with coronary artery disease. , 2001, Mutation research.

[74]  N. Alp,et al.  Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[75]  J. Griffin,et al.  The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice. , 2012, Free radical biology & medicine.

[76]  G. Duda,et al.  Insights into Mesenchymal Stem Cell Aging: Involvement of Antioxidant Defense and Actin Cytoskeleton , 2009, Stem cells.

[77]  Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species Through Effects on Smooth Muscle Cells and Monocytes and Correlates With Higher-Risk Plaques in Humans , 2013, Circulation.

[78]  Megan Scudellari.  To stay young, kill zombie cells , 2017, Nature.

[79]  E. Lakatta,et al.  Calpain-1 Regulation of Matrix Metalloproteinase 2 Activity in Vascular Smooth Muscle Cells Facilitates Age-Associated Aortic Wall Calcification and Fibrosis , 2012, Hypertension.

[80]  R. Townsend,et al.  Arterial compliance in the elderly: its effect on blood pressure measurement and cardiovascular outcomes. , 2009, Clinics in geriatric medicine.

[81]  J. Deursen.  The role of senescent cells in ageing , 2014, Nature.

[82]  Regina Brunauer,et al.  Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan , 2007, Aging cell.

[83]  Cynthia A. Reinhart-King,et al.  Indentation measurements of the subendothelial matrix in bovine carotid arteries. , 2011, Journal of biomechanics.

[84]  R. Schlegel,et al.  Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells. , 1996, The Journal of clinical investigation.

[85]  A. Tedgui,et al.  Increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats. , 1995, The American journal of physiology.

[86]  Megan F. Cole,et al.  Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells , 2005, Cell.

[87]  Y. Ni,et al.  Inhibited atherosclerotic plaque formation by local administration of magnetically labeled endothelial progenitor cells (EPCs) in a rabbit model. , 2009, Atherosclerosis.

[88]  S. Blankenberg,et al.  Deficiency of Glutathione Peroxidase-1 Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[89]  A. Verin,et al.  Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway. , 2011, American journal of physiology. Cell physiology.

[90]  N. Chandel,et al.  Physiological roles of mitochondrial reactive oxygen species. , 2012, Molecular cell.

[91]  S. Hung,et al.  Oct4 and Nanog directly regulate Dnmt1 to maintain self-renewal and undifferentiated state in mesenchymal stem cells. , 2012, Molecular cell.

[92]  M. Beal,et al.  Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age , 1992, Nature Genetics.

[93]  N. Cook,et al.  Salt Sensitivity of Blood Pressure: A Scientific Statement From the American Heart Association. , 2016, Hypertension.

[94]  Haoyue Zhang,et al.  Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1 , 2014, Proceedings of the National Academy of Sciences.

[95]  J. Imbs,et al.  Effects of dietary salt changes on renal renin-angiotensin system in rats. , 2002, American journal of physiology. Renal physiology.

[96]  P. Kirkpatrick,et al.  Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis: Effects of Telomerase and Oxidative Stress , 2006, Circulation research.

[97]  P. Tsao,et al.  eNOS Activity Is Reduced in Senescent Human Endothelial Cells: Preservation by hTERT Immortalization , 2001, Circulation research.

[98]  Helim Aranda-Espinoza,et al.  Endothelial cell substrate stiffness influences neutrophil transmigration via myosin light chain kinase-dependent cell contraction. , 2011, Blood.

[99]  J. Montani,et al.  Role of p38 mitogen-activated protein kinase in vascular endothelial aging: Interaction with Arginase-II and S6K1 signaling pathway , 2015, Aging.

[100]  N. Venediktova,et al.  Oxidative stress induces degradation of mitochondrial DNA , 2009, Nucleic acids research.

[101]  N. Carter,et al.  A DNA damage checkpoint response in telomere-initiated senescence , 2003, Nature.

[102]  E. Lakatta,et al.  MFG‐E8 activates proliferation of vascular smooth muscle cells via integrin signaling , 2012, Aging cell.

[103]  J. Panés,et al.  Direct evidence of leukocyte adhesion in arterioles by angiotensin II. , 2004, Blood.

[104]  Christian Gluud,et al.  Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. , 2007, JAMA.

[105]  Liangbiao Chen,et al.  Differentiation of human embryonic stem cells into smooth muscle cells in adherent monolayer culture. , 2006, Biochemical and biophysical research communications.

[106]  S. Badylak,et al.  A perivascular origin for mesenchymal stem cells in multiple human organs. , 2008, Cell stem cell.

[107]  T. Strandberg,et al.  The roles of senescence and telomere shortening in cardiovascular disease , 2013, Nature Reviews Cardiology.

[108]  H. Wellens,et al.  Biphasic pattern of cell turnover characterizes the progression from fatty streaks to ruptured human atherosclerotic plaques. , 1999, Cardiovascular research.

[109]  V. Salomaa,et al.  Telomere Length in Old Age and Cholesterol Across the Life Course , 2011, Journal of the American Geriatrics Society.

[110]  J. Kovacic,et al.  Update on the use of stem cells for cardiac disease , 2005, Internal medicine journal.

[111]  Qingbo Xu,et al.  Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. , 2004, The Journal of clinical investigation.

[112]  T. Zglinicki.  Oxidative stress shortens telomeres , 2002 .

[113]  P. Libby,et al.  Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme. , 1995, The American journal of pathology.

[114]  I. Bellantuono,et al.  Study of Telomere Length Reveals Rapid Aging of Human Marrow Stromal Cells following In Vitro Expansion , 2004, Stem cells.

[115]  Robin A. J. Smith,et al.  The mitochondria‐targeted anti‐oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients , 2010, Liver international : official journal of the International Association for the Study of the Liver.

[116]  Kerstin Schneeberger,et al.  Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer , 2012, EMBO molecular medicine.

[117]  L. Gordon,et al.  Hutchinson–Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[118]  D. Lio,et al.  Are Endothelial Progenitor Cells the Real Solution for Cardiovascular Diseases? Focus on Controversies and Perspectives , 2015, BioMed research international.

[119]  Aihua Xia,et al.  Mesenchymal Stem Cells Stabilize Atherosclerotic Vulnerable Plaque by Anti-Inflammatory Properties , 2015, PloS one.

[120]  Ruogang Zhao,et al.  NANOG Restores Contractility of Mesenchymal Stem Cell-Based Senescent Microtissues. , 2017, Tissue engineering. Part A.

[121]  T. Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres , 2005 .

[122]  T. Littlewood,et al.  Statins Use a Novel Nijmegen Breakage Syndrome-1–Dependent Pathway to Accelerate DNA Repair in Vascular Smooth Muscle Cells , 2008, Circulation research.

[123]  G. Desideri,et al.  Angiotensin II increases the release of endothelin-1 from human cultured endothelial cells but does not regulate its circulating levels. , 1999, Clinical science.

[124]  P. Aljama,et al.  Carbamylated low‐density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[125]  Y Taya,et al.  The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. , 2000, Genes & development.

[126]  Sam W. Lee,et al.  Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence , 2010, Journal of Cell Science.

[127]  Y. Yoon,et al.  Decreasing mitochondrial fission diminishes vascular smooth muscle cell migration and ameliorates intimal hyperplasia. , 2015, Cardiovascular research.

[128]  Leslie A. Smith,et al.  Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice , 2016, Aging cell.

[129]  A. Garnier,et al.  Hutchinson–Gilford progeria syndrome as a model for vascular aging , 2015, Biogerontology.

[130]  P. Muñoz-Cánoves,et al.  Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells , 2013, The FEBS journal.

[131]  Danica Chen,et al.  Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. , 2010, Cell metabolism.

[132]  Yong Wang,et al.  Total body irradiation selectively induces murine hematopoietic stem cell senescence. , 2006, Blood.

[133]  W. Fibbe,et al.  Mesenchymal stromal cells: sensors and switchers of inflammation. , 2013, Cell stem cell.

[134]  C. R. Esteban,et al.  In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming , 2016, Cell.

[135]  M. Runge,et al.  Mitochondrial Integrity and Function in Atherogenesis , 2002, Circulation.

[136]  M. Esteller,et al.  Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome , 2013, Epigenetics.

[137]  E. Lakatta,et al.  Altered Regulation of Matrix Metalloproteinase-2 in Aortic Remodeling During Aging , 2002, Hypertension.

[138]  Hyun-Jai Cho,et al.  Direct Conversion of Adult Skin Fibroblasts to Endothelial Cells by Defined Factors , 2014, Circulation.

[139]  Zhongkui Hong,et al.  Increased vascular smooth muscle cell stiffness: a novel mechanism for aortic stiffness in hypertension. , 2013, American journal of physiology. Heart and circulatory physiology.

[140]  L. Ignarro,et al.  Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes , 2014, Proceedings of the National Academy of Sciences.

[141]  R. Caldwell,et al.  Peroxynitrite Mediates Diabetes-Induced Endothelial Dysfunction: Possible Role of Rho Kinase Activation , 2010, Experimental diabetes research.

[142]  M. Ikeda,et al.  Reduction of nitric oxide producing activity associated with in vitro aging in cultured human umbilical vein endothelial cell. , 1993, Biochemical and biophysical research communications.

[143]  Eduardo Sontag,et al.  Transcriptional control of human p53-regulated genes , 2008, Nature Reviews Molecular Cell Biology.

[144]  N. Kaminski,et al.  Aging mesenchymal stem cells fail to protect because of impaired migration and antiinflammatory response. , 2014, American journal of respiratory and critical care medicine.

[145]  K. Amann,et al.  Increased expression of endothelin-1 and inducible nitric oxide synthase isoform II in aging arteries in vivo: implications for atherosclerosis. , 2001, Biochemical and biophysical research communications.

[146]  Y. Yoon,et al.  Intramyocardial Transplantation of Autologous Endothelial Progenitor Cells for Therapeutic Neovascularization of Myocardial Ischemia , 2003, Circulation.

[147]  Da-Zhi Wang,et al.  Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression , 2004, Nature.

[148]  E. Lakatta,et al.  Proinflammation: the key to arterial aging , 2014, Trends in Endocrinology & Metabolism.

[149]  H. Ohgushi,et al.  Forced expression of Sox2 or Nanog in human bone marrow derived mesenchymal stem cells maintains their expansion and differentiation capabilities. , 2008, Experimental cell research.

[150]  S. Wong,et al.  Pericytes, mesenchymal stem cells and their contributions to tissue repair. , 2015, Pharmacology & therapeutics.

[151]  T. Kawamoto,et al.  Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction. , 2008, Cardiovascular research.

[152]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[153]  T. Imanishi,et al.  Endothelial progenitor cell senescence is accelerated in both experimental hypertensive rats and patients with essential hypertension , 2005, Journal of hypertension.

[154]  C. Conover,et al.  Senescent intimal foam cells are deleterious at all stages of atherosclerosis , 2016, Science.

[155]  Manuel Serrano,et al.  The Hallmarks of Aging , 2013, Cell.

[156]  D. Eatman,et al.  Alterations in Aldosterone and Angiotensin II Levels in Salt-Induced Hypertension , 2005, Clinical and experimental hypertension.

[157]  Song Liu,et al.  Nanog Reverses the Effects of Organismal Aging on Mesenchymal Stem Cell Proliferation and Myogenic Differentiation Potential , 2012, Stem cells.

[158]  C. Iadecola,et al.  NF-κB Regulates Phagocytic NADPH Oxidase by Inducing the Expression of gp91phox* , 2006, Journal of Biological Chemistry.

[159]  Chen Yan,et al.  Downregulation of Dynamin-Related Protein 1 Contributes to Impaired Autophagic Flux and Angiogenic Function in Senescent Endothelial Cells , 2015, Arteriosclerosis, thrombosis, and vascular biology.

[160]  T. Lüscher,et al.  Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ET(A)-receptor antagonist. , 1997, Circulation.

[161]  Yi-zhou Jiang,et al.  Hemodynamic Disturbed Flow Induces Differential DNA Methylation of Endothelial Kruppel-Like Factor 4 Promoter In Vitro and In Vivo , 2014, Circulation research.

[162]  Y. Ikeda,et al.  Endothelial Differentiation Potential of Human Monocyte‐Derived Multipotential Cells , 2006, Stem cells.

[163]  Rong Wang,et al.  Endothelial cell apoptosis is responsible for the formation of coronary thrombotic atherosclerotic plaques. , 2009, The Tohoku journal of experimental medicine.

[164]  I. Komuro,et al.  Angiotensin II Induces Premature Senescence of Vascular Smooth Muscle Cells and Accelerates the Development of Atherosclerosis via a p21-Dependent Pathway , 2006, Circulation.

[165]  Xiaoshu Cheng,et al.  PI3K/Akt/uncoupling protein 2 signaling pathway may be involved in cell senescence and apoptosis induced by angiotensin II in human vascular endothelial cells , 2014, Molecular Biology Reports.

[166]  Yusuke Nakamura,et al.  p53AIP1, a Potential Mediator of p53-Dependent Apoptosis, and Its Regulation by Ser-46-Phosphorylated p53 , 2000, Cell.

[167]  E. Falk,et al.  Smooth Muscle Cells in Atherosclerosis Originate From the Local Vessel Wall and Not Circulating Progenitor Cells in ApoE Knockout Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[168]  B. Christy,et al.  Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. , 2000, The Journal of clinical investigation.

[169]  M. Rondaij,et al.  KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. , 2006, Blood.

[170]  P. Salvén,et al.  Generation of Functional Blood Vessels from a Single c-kit+ Adult Vascular Endothelial Stem Cell , 2012, PLoS biology.

[171]  Richard T. Lee,et al.  Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. , 2004, The Journal of clinical investigation.

[172]  D. Levy,et al.  Association of Leukocyte Telomere Length With Circulating Biomarkers of the Renin-Angiotensin-Aldosterone System: The Framingham Heart Study , 2008, Circulation.

[173]  A. Quyyumi,et al.  Circulating CD34+ Progenitor Cells and Risk of Mortality in a Population With Coronary Artery Disease , 2015, Circulation research.

[174]  J. Pickering,et al.  Angiotensin II stimulates collagen synthesis in human vascular smooth muscle cells. Involvement of the AT(1) receptor, transforming growth factor-beta, and tyrosine phosphorylation. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[175]  S. Nemoto,et al.  SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1α* , 2005, Journal of Biological Chemistry.

[176]  Olivier Elemento,et al.  Efficient Direct Reprogramming of Mature Amniotic Cells into Endothelial Cells by ETS Factors and TGFβ Suppression , 2012, Cell.

[177]  Jing Zhang,et al.  Increased Aortic Calpain-1 Activity Mediates Age-Associated Angiotensin II Signaling of Vascular Smooth Muscle Cells , 2008, PloS one.

[178]  T. D. Pugh,et al.  Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging , 2005, Science.

[179]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.

[180]  S. Chien,et al.  Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. , 2011, Physiological reviews.

[181]  Andrea Bodnar,et al.  Human Endothelial Cell Life Extension by Telomerase Expression* , 1999, The Journal of Biological Chemistry.

[182]  D. Broccoli,et al.  p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. , 1999, Science.

[183]  A. Giaccia,et al.  Age Decreases Endothelial Progenitor Cell Recruitment Through Decreases in Hypoxia-Inducible Factor 1α Stabilization During Ischemia , 2007, Circulation.

[184]  Ming-Yu Liu,et al.  Mitochondrial Fission of Smooth Muscle Cells Is Involved in Artery Constriction , 2016, Hypertension.

[185]  R. Alexander,et al.  PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases. , 2015, Cell reports.

[186]  O. Tricot,et al.  Relation between endothelial cell apoptosis and blood flow direction in human atherosclerotic plaques. , 2000, Circulation.

[187]  A. Vercesi,et al.  Oxidative stress in atherosclerosis‐prone mouse is due to low antioxidant capacity of mitochondria , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[188]  B. Lim,et al.  Effects of ectopic Nanog and Oct4 overexpression on mesenchymal stem cells. , 2009, Stem cells and development.

[189]  M. Denkinger,et al.  Hematopoietic stem cell aging. , 2014, Current opinion in immunology.

[190]  J. Isner,et al.  Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells , 2002, Circulation.

[191]  B. Kang,et al.  Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. , 2015, Free radical biology & medicine.

[192]  C. Hill,et al.  Incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in endothelium-derived hyperpolarizing factor-mediated responses. , 2000, Circulation research.

[193]  Yasmin,et al.  Variation in the Human Matrix Metalloproteinase-9 Gene Is Associated With Arterial Stiffness in Healthy Individuals , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[194]  D. Bruemmer,et al.  Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes , 2017, Arteriosclerosis, thrombosis, and vascular biology.

[195]  D. Seals,et al.  Mitochondria‐targeted antioxidant (MitoQ) ameliorates age‐related arterial endothelial dysfunction in mice , 2014, The Journal of physiology.

[196]  A. Kumagai,et al.  Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. , 2000, Genes & development.

[197]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[198]  Jeffrey A. Jones,et al.  Relation of Murine Thoracic Aortic Structural and Cellular Changes With Aging to Passive and Active Mechanical Properties , 2015, Journal of the American Heart Association.

[199]  M. Joyner,et al.  Aging Is Associated With Reduced Prostacyclin-Mediated Dilation in the Human Forearm , 2009, Hypertension.

[200]  J. Yates,et al.  Recapitulation of premature aging with iPSCs from Hutchinson-Gilford progeria syndrome , 2011, Nature.

[201]  M. Weinberger,et al.  Salt sensitivity of blood pressure in humans. , 1996, Hypertension.

[202]  Arshed A. Quyyumi,et al.  Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular Risk , 2003 .

[203]  G. Zhong,et al.  OxLDL stimulates cell proliferation through a general induction of cell cycle proteins. , 2003, American journal of physiology. Heart and circulatory physiology.

[204]  S. Mieno,et al.  Implantation of Mesenchymal Stem Cells Overexpressing Endothelial Nitric Oxide Synthase Improves Right Ventricular Impairments Caused by Pulmonary Hypertension , 2006, Circulation.

[205]  D. Seals,et al.  Aging is associated with greater nuclear NFκB, reduced IκBα, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans , 2008, Aging cell.

[206]  V. Dulic,et al.  DNA damage checkpoint kinase Chk2 triggers replicative senescence , 2004, The EMBO journal.

[207]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[208]  J. Issa,et al.  Epigenetic changes in estrogen receptor beta gene in atherosclerotic cardiovascular tissues and in-vitro vascular senescence. , 2007, Biochimica et biophysica acta.

[209]  M. Ushio-Fukai,et al.  Low‐Dose 6‐Bromoindirubin‐3′‐oxime Induces Partial Dedifferentiation of Endothelial Cells to Promote Increased Neovascularization , 2014, Stem cells.

[210]  Dong Wook Han,et al.  Generation of induced pluripotent stem cells using recombinant proteins. , 2009, Cell stem cell.

[211]  Elisa Cibrario Rocchietti,et al.  Persistent DNA damage-induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells , 2015, Journal of cellular and molecular medicine.

[212]  R. Stewart,et al.  Lineage Reprogramming of Fibroblasts into Proliferative Induced Cardiac Progenitor Cells by Defined Factors. , 2016, Cell stem cell.

[213]  N. Lévy,et al.  Prelamin A accumulation in endothelial cells induces premature senescence and functional impairment. , 2014, Atherosclerosis.

[214]  Yan-hong Guo,et al.  Dysregulation of HSG triggers vascular proliferative disorders , 2004, Nature Cell Biology.

[215]  G. Mitchell.  Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. , 2008, Journal of applied physiology.

[216]  Xin Lu,et al.  ASPP proteins specifically stimulate the apoptotic function of p53. , 2001, Molecular cell.

[217]  M. Bennett,et al.  Vascular Smooth Muscle Cell Sirtuin 1 Protects Against DNA Damage and Inhibits Atherosclerosis , 2013, Circulation.

[218]  Sami Alom Ruiz,et al.  Mechanical tugging force regulates the size of cell–cell junctions , 2010, Proceedings of the National Academy of Sciences.

[219]  M. Kelm,et al.  Impaired progenitor cell activity in age-related endothelial dysfunction. , 2005, Journal of the American College of Cardiology.

[220]  M. Blasco,et al.  Mice Deficient in Telomerase Activity Develop Hypertension Because of an Excess of Endothelin Production , 2006, Circulation.

[221]  I. Komuro,et al.  Endothelial Cell Senescence in Human Atherosclerosis: Role of Telomere in Endothelial Dysfunction , 2002, Circulation.

[222]  Lu Gao,et al.  Effects of Inflammatory Factors on Mesenchymal Stem Cells and Their Role in the Promotion of Tumor Angiogenesis in Colon Cancer* , 2011, The Journal of Biological Chemistry.

[223]  Yan-hong Guo,et al.  Overexpression of Mitofusin 2 inhibited oxidized low-density lipoprotein induced vascular smooth muscle cell proliferation and reduced atherosclerotic lesion formation in rabbit. , 2007, Biochemical and biophysical research communications.

[224]  R. Goldman,et al.  Disruption of Nuclear Lamin Organization Blocks the Elongation Phase of DNA Replication , 2000, The Journal of cell biology.

[225]  A. Zeiher,et al.  Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI): final 5-year results suggest long-term safety and efficacy , 2011, Clinical Research in Cardiology.

[226]  P. Goldschmidt-Clermont,et al.  Inactivation of Monocarboxylate Transporter MCT3 by DNA Methylation in Atherosclerosis , 2005, Circulation.

[227]  T. Wirth,et al.  Global DNA methylation analysis of human atherosclerotic plaques reveals extensive genomic hypomethylation and reactivation at imprinted locus 14q32 involving induction of a miRNA cluster. , 2015, European heart journal.

[228]  T. V. van Berkel,et al.  Aorta of ApoE-Deficient Mice Responds to Atherogenic Stimuli by a Prelesional Increase and Subsequent Decrease in the Expression of Antioxidant Enzymes , 2003, Circulation research.

[229]  E. Oberlin,et al.  The Vascular Wall as a Source of Stem Cells , 2005, Annals of the New York Academy of Sciences.

[230]  F. Francini,et al.  Sphingosine 1-phosphate induces differentiation of adipose tissue-derived mesenchymal stem cells towards smooth muscle cells , 2009, Cellular and Molecular Life Sciences.

[231]  S. Homma,et al.  Neovascularization of ischemic myocardium by human bone-marrow–derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function , 2001, Nature Medicine.

[232]  M. Yoder,et al.  Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. , 2005, Blood.

[233]  U. de Faire,et al.  Telomere length is associated with ACE I/D polymorphism in hypertensive patients with left ventricular hypertrophy , 2013, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[234]  M. Bennett,et al.  Senescent Vascular Smooth Muscle Cells Drive Inflammation Through an Interleukin-1α–Dependent Senescence-Associated Secretory Phenotype , 2015, Arteriosclerosis, thrombosis, and vascular biology.

[235]  T. Tsuruo,et al.  Differentiation of Lymphatic Endothelial Cells From Embryonic Stem Cells on OP9 Stromal Cells , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[236]  Y. Ouchi,et al.  Sirt1 modulates premature senescence-like phenotype in human endothelial cells. , 2007, Journal of molecular and cellular cardiology.

[237]  U. Laufs,et al.  Post-transcriptional Regulation of Endothelial Nitric Oxide Synthase mRNA Stability by Rho GTPase* , 1998, The Journal of Biological Chemistry.

[238]  Konstantinos Konstantopoulos,et al.  Cancer cell motility: lessons from migration in confined spaces , 2016, Nature Reviews Cancer.

[239]  P. Mistriotis,et al.  Clonal multipotency and effect of long-term in vitro expansion on differentiation potential of human hair follicle derived mesenchymal stem cells. , 2012, Stem cell research.

[240]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[241]  T. Finkel.  From Sulfenylation to Sulfhydration: What a Thiolate Needs to Tolerate , 2012, Science Signaling.

[242]  Y Taya,et al.  Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. , 1998, Science.

[243]  Haruchika Masuda,et al.  Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization , 1999, Nature Medicine.

[244]  B. Herbert,et al.  Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factor‐α via the p38 mitogen‐activated protein kinase pathway , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[245]  J. Campisi,et al.  Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion , 2009, Nature Cell Biology.

[246]  S. Provencher,et al.  Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. , 2014, Cell metabolism.

[247]  S. Elledge,et al.  Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[248]  J. Skurnick,et al.  Age dependent aneuploidy and telomere length of the human vascular endothelium. , 2001, Atherosclerosis.

[249]  P. Mericko,et al.  Megakaryoblastic Leukemia Factor-1 Transduces Cytoskeletal Signals and Induces Smooth Muscle Cell Differentiation from Undifferentiated Embryonic Stem Cells* , 2004, Journal of Biological Chemistry.

[250]  R Cancedda,et al.  Repair of large bone defects with the use of autologous bone marrow stromal cells. , 2001, The New England journal of medicine.

[251]  S. Andreadis,et al.  Derivation of functional smooth muscle cells from multipotent human hair follicle mesenchymal stem cells. , 2010, Tissue engineering. Part A.

[252]  J. Wang,et al.  Fibroblasts and myofibroblasts in wound healing: force generation and measurement. , 2011, Journal of tissue viability.

[253]  F. Collins,et al.  Cardiovascular Pathology in Hutchinson-Gilford Progeria: Correlation With the Vascular Pathology of Aging , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[254]  Hong Yang,et al.  Retardation of Atherosclerosis by Overexpression of Catalase or Both Cu/Zn-Superoxide Dismutase and Catalase in Mice Lacking Apolipoprotein E , 2004, Circulation research.

[255]  James A Russell,et al.  Functional tissue-engineered blood vessels from bone marrow progenitor cells. , 2007, Cardiovascular research.

[256]  D. Coutu,et al.  Inhibition of cellular senescence by developmentally regulated FGF receptors in mesenchymal stem cells. , 2011, Blood.

[257]  J. Issa,et al.  Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. , 1999, Cardiovascular research.

[258]  P. Kirkpatrick,et al.  Differential cyclin E expression in human in-stent stenosis smooth muscle cells identifies targets for selective anti-restenosis therapy. , 2003, Cardiovascular research.

[259]  Robert V Farese,et al.  Sirt3 Regulates Fatty Acid Oxidation via Reversible Enzyme Deacetylation Hhs Public Access Supplementary Material , 2022 .

[260]  E. Lakatta,et al.  Matrix Metalloproteinase 2 Activation of Transforming Growth Factor-&bgr;1 (TGF-&bgr;1) and TGF-&bgr;1–Type II Receptor Signaling Within the Aged Arterial Wall , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[261]  Robert S. Balaban,et al.  Mitochondria, Oxidants, and Aging , 2005, Cell.

[262]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[263]  Abena B. Redwood,et al.  A new pathway that regulates 53BP1 stability implicates Cathepsin L and vitamin D in DNA repair , 2011, EMBO Journal.

[264]  G. Owens,et al.  A Transforming Growth Factor β (TGFβ) Control Element Drives TGFβ-induced Stimulation of Smooth Muscle α-Actin Gene Expression in Concert with Two CArG Elements* , 1997, The Journal of Biological Chemistry.

[265]  Dennis E. Discher,et al.  Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation , 2013, Science.

[266]  Robert Lanza,et al.  Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. , 2009, Cell stem cell.

[267]  Jay X. Tang,et al.  Neutrophil morphology and migration are affected by substrate elasticity. , 2009, Blood.

[268]  J. Fredberg,et al.  Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces. , 2011, American Journal of Physiology - Cell Physiology.

[269]  B. Williams,et al.  Angiotensin II–Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways , 2008, Circulation research.

[270]  S. Samuel,et al.  The endothelium: influencing vascular smooth muscle in many ways. , 2012, Canadian journal of physiology and pharmacology.

[271]  Zhenyu Tang,et al.  Differentiation of Multipotent Vascular Stem Cells Contributes to Vascular Diseases , 2012, Nature Communications.

[272]  S. Andreadis,et al.  Contractile smooth muscle cells derived from hair-follicle stem cells. , 2008, Cardiovascular research.

[273]  L. Niklason,et al.  Small‐diameter human vessel wall engineered from bone marrow‐derived mesenchymal stem cells (hMSCs) , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[274]  P. Hammerstein,et al.  Morpho-dynamic changes of mitochondria during ageing of human endothelial cells , 2005, Mechanisms of Ageing and Development.

[275]  Dean Y. Li,et al.  Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability , 2012, Nature.

[276]  S. Archer,et al.  PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. , 2013, American journal of respiratory and critical care medicine.

[277]  M. Manjanatha,et al.  Accumulation of point mutations in mitochondrial DNA of aging mice. , 2003, Mutation research.

[278]  B. Sun,et al.  Angiotensin AT1 receptor antagonists exert anti‐inflammatory effects in spontaneously hypertensive rats , 2007, British journal of pharmacology.

[279]  W. Hofmann,et al.  Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. , 2004, Journal of the American College of Cardiology.

[280]  C. Shao,et al.  NANOG has a role in mesenchymal stem cells' immunomodulatory effect. , 2011, Stem cells and development.

[281]  G. Owens,et al.  Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. , 2012, Annual review of physiology.

[282]  S. Andreadis,et al.  Cadherin-11 regulates both mesenchymal stem cell differentiation into smooth muscle cells and the development of contractile function in vivo , 2014, Journal of Cell Science.

[283]  Z. Ungvari,et al.  Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats. , 2008, American journal of physiology. Heart and circulatory physiology.

[284]  John M Sedivy,et al.  Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). , 2004, Molecular cell.

[285]  Arif Yurdagul,et al.  Molecular Mechanisms of Collagen Isotype-Specific Modulation of Smooth Muscle Cell Phenotype , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[286]  H. Sugiyama,et al.  Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries. , 2006, American journal of hypertension.

[287]  S. Chellappan,et al.  TNF-α-mediated proliferation of vascular smooth muscle cells involves Raf-1-mediated inactivation of Rb and transcription of E2F1-regulated genes , 2012, Cell cycle.

[288]  Julie V. Harness,et al.  Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. , 2011, Cell stem cell.

[289]  Peter Wernet,et al.  Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans , 2002 .

[290]  Laura S. Shankman,et al.  KLF4 Dependent Phenotypic Modulation of SMCs Plays a Key Role in Atherosclerotic Plaque Pathogenesis , 2015, Nature Medicine.

[291]  J. Isner,et al.  VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells , 1999, The EMBO journal.

[292]  J. Kuiper,et al.  Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development , 2015, Scientific Reports.

[293]  Timothy J. Laurent,et al.  Conversion of Human Fibroblasts to Functional Endothelial Cells by Defined Factors , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[294]  François Bordeleau,et al.  Cooperative effects of matrix stiffness and fluid shear stress on endothelial cell behavior. , 2015, Biophysical journal.

[295]  J. Tschopp,et al.  A role for mitochondria in NLRP3 inflammasome activation , 2011, Nature.

[296]  K. Pollok,et al.  Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. , 2004, Blood.

[297]  Elliot L Elson,et al.  Short Communication: Vascular Smooth Muscle Cell Stiffness As a Mechanism for Increased Aortic Stiffness With Aging , 2010, Circulation research.

[298]  C. DeSouza,et al.  Aging and endothelial progenitor cell telomere length in healthy men , 2009, Clinical chemistry and laboratory medicine.

[299]  Esteban Ballestar,et al.  DNA Methylation Polymorphisms Precede Any Histological Sign of Atherosclerosis in Mice Lacking Apolipoprotein E* , 2004, Journal of Biological Chemistry.

[300]  E. Fleck,et al.  TNF-α–Induced Migration of Vascular Smooth Muscle Cells Is MAPK Dependent , 1999 .

[301]  T. Willson,et al.  Synthetic LXR ligand inhibits the development of atherosclerosis in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[302]  P. Poole‐Wilson,et al.  Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1 , 2007, Circulation research.

[303]  Yuzhi Zhang,et al.  Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[304]  Koichi Hattori,et al.  Young Adult Bone Marrow–Derived Endothelial Precursor Cells Restore Aging-Impaired Cardiac Angiogenic Function , 2002, Circulation research.

[305]  Begoña Aguado,et al.  Global variability in gene expression and alternative splicing is modulated by mitochondrial content , 2015, Genome research.

[306]  I. Varela,et al.  Splicing-Directed Therapy in a New Mouse Model of Human Accelerated Aging , 2011, Science Translational Medicine.

[307]  A. Donato,et al.  TNF-α impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity. , 2012, American journal of physiology. Heart and circulatory physiology.

[308]  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) , 2002 .

[309]  De-Pei Liu,et al.  SIRT1 Acts as a Modulator of Neointima Formation Following Vascular Injury in Mice , 2011, Circulation research.

[310]  G. Evan,et al.  Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. , 1995, The Journal of clinical investigation.

[311]  R. Cawthon,et al.  Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries. , 2013, American journal of physiology. Heart and circulatory physiology.

[312]  M. Bennett,et al.  Vascular smooth muscle cell senescence in atherosclerosis. , 2006, Cardiovascular research.

[313]  Z. Ungvari,et al.  Increased mitochondrial H2O2 production promotes endothelial NF- B activation in aged rat arteries , 2007 .

[314]  J. Lammerding,et al.  Lamin A/C and emerin regulate MKL1/SRF activity by modulating actin dynamics , 2013, Nature.

[315]  Lorenzo Galluzzi,et al.  Mitochondrial membrane permeabilization in cell death. , 2007, Physiological reviews.

[316]  David A. Scott,et al.  In vivo genome editing using Staphylococcus aureus Cas9 , 2015, Nature.

[317]  De-Pei Liu,et al.  Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. , 2008, Cardiovascular research.

[318]  R Clinton Webb,et al.  Smooth muscle contraction and relaxation. , 2003, Advances in physiology education.

[319]  G. D. De Meyer,et al.  Elevated Levels of Oxidative DNA Damage and DNA Repair Enzymes in Human Atherosclerotic Plaques , 2002, Circulation.

[320]  N. LeBrasseur,et al.  Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders , 2011, Nature.

[321]  J. Ramires,et al.  Morphology of the Internal Elastic Lamina in Arteries from Pulmonary Hypertensive Patients: a Confocal Laser Microscopy Study , 2003, Modern Pathology.

[322]  E. Lakatta,et al.  Brain ouabain stimulates peripheral marinobufagenin via angiotensin II signalling in NaCl-loaded Dahl-S rats , 2005, Journal of hypertension.

[323]  S. Archer,et al.  Dynamin-Related Protein 1–Mediated Mitochondrial Mitotic Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells and Offers a Novel Therapeutic Target in Pulmonary Hypertension , 2012, Circulation research.

[324]  T. Spector,et al.  A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length , 2009, Journal of Medical Genetics.

[325]  Thomas P. Lozito,et al.  Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs , 2011, Journal of cellular physiology.

[326]  N. Fineberg,et al.  Sodium and Volume Sensitivity of Blood Pressure Age and Pressure Change Over Time , 1991, Hypertension.

[327]  Gene Kim,et al.  Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. , 2009, The Journal of clinical investigation.

[328]  G. Martin,et al.  Age and Human Regenerative Capacity Impact of Cardiovascular Risk Factors. , 2016, Circulation research.

[329]  T. Asano,et al.  Blockade of the Nuclear Factor-&kgr;B Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans , 2012, Circulation.

[330]  P. Vanhoutte,et al.  Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension. , 2008, Physiological genomics.

[331]  Yuzhi Zhang,et al.  Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. , 2005, The Journal of clinical investigation.

[332]  K. Kaibuchi,et al.  Rho-kinase phosphorylates eNOS at threonine 495 in endothelial cells. , 2007, Biochemical and biophysical research communications.

[333]  E. Lakatta,et al.  Endogenous Ligand of &agr;1 Sodium Pump, Marinobufagenin, Is a Novel Mediator of Sodium Chloride–Dependent Hypertension , 2002, Circulation.

[334]  Thomas A. Einhorn,et al.  Fracture healing in the elderly patient , 2006, Experimental Gerontology.

[335]  W. R. Taylor,et al.  Overexpression of Catalase in Vascular Smooth Muscle Cells Prevents the Formation of Abdominal Aortic Aneurysms , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[336]  R. Sachidanandam,et al.  A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis , 2013, Cell Death and Differentiation.

[337]  Masashi Narita,et al.  Reversal of human cellular senescence: roles of the p53 and p16 pathways , 2003, The EMBO journal.

[338]  Cynthia A. Reinhart-King,et al.  Age-Related Intimal Stiffening Enhances Endothelial Permeability and Leukocyte Transmigration , 2011, Science Translational Medicine.

[339]  T. Misteli,et al.  Repression of the Antioxidant NRF2 Pathway in Premature Aging , 2016, Cell.

[340]  M. Blasco,et al.  Short telomeres protect from diet‐induced atherosclerosis in apolipoprotein E‐null mice , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[341]  Ching-Fang Chang,et al.  Immortalization without neoplastic transformation of human mesenchymal stem cells by transduction with HPV16 E6/E7 genes , 2004, International journal of cancer.

[342]  M. Bennett,et al.  Vascular Smooth Muscle Cell Senescence Promotes Atherosclerosis and Features of Plaque Vulnerability , 2015, Circulation.

[343]  A. Bokov,et al.  Is the oxidative stress theory of aging dead? , 2009, Biochimica et biophysica acta.