Age-dependent impairment of angiogenesis.

BACKGROUND The effect of aging on angiogenesis in ischemic vascular disease has not been studied. Accordingly, we investigated the hypothesis that angiogenesis is impaired as a function of age. METHODS AND RESULTS Forty days after the resection of 1 femoral artery, collateral vessel development was significantly impaired in old (aged 4 to 5 years; n=7) versus young (aged 6 to 8 months; n=6) New Zealand White (NZW) rabbits on the basis of reduced hindlimb perfusion (ischemic: normal blood pressure ratio=0.58+/-0.05 versus 0.77+/-0.06; P<0.005), reduced number of angiographically visible vessels (angiographic score=0.48+/-0.05 versus 0.70+/-0.05; P<0.01), and lower capillary density in the ischemic limb (130.3+/-5.8/mm2 versus 171.4+/-9.5/mm2; P<0.001). Angiogenesis was also impaired in old (aged 2 years) versus young (aged 12 weeks) mice as shown by reduced hindlimb perfusion (measured by laser Doppler imaging) and lower capillary density (353.0+/-14.3/mm2 versus 713.3+/-63.4/mm2; P<0.01). Impaired angiogenesis in old animals was the result of impaired endothelial function (lower basal NO release and decreased vasodilation in response to acetylcholine) and a lower expression of vascular endothelial growth factor (VEGF) in ischemic tissues (by Northern blot, Western blot, and immunohistochemistry). When recombinant VEGF protein was administered to young and old rabbits, both groups exhibited a significant and similar increase in blood pressure ratio, angiographic score, and capillary density. CONCLUSIONS Angiogenesis responsible for collateral development in limb ischemia is impaired with aging; responsible mechanisms include age-related endothelial dysfunction and reduced VEGF expression. Advanced age, however, does not preclude augmentation of collateral vessel development in response to exogenous angiogenic cytokines.

[1]  J. Isner,et al.  Time course of increased cellular proliferation in collateral arteries after administration of vascular endothelial growth factor in a rabbit model of lower limb vascular insufficiency. , 1995, The American journal of pathology.

[2]  S. Nagataki,et al.  Characterization of T cells transmigrating through human endothelial cells in patients with HTLV-I-associated myelopathy. , 1997, Immunobiology.

[3]  J. Pearlman,et al.  Magnetic resonance mapping demonstrates benefits of VEGF–induced myocardial angiogenesis , 1995, Nature Medicine.

[4]  R. Tomanek,et al.  Remodeling of coronary vessels during aging in purebred beagles. , 1991, Circulation research.

[5]  J. Isner,et al.  Reciprocal relation between VEGF and NO in the regulation of endothelial integrity , 1997, Nature Medicine.

[6]  D. Heistad,et al.  Age‐Related Changes in Release of Endothelium‐Derived Relaxing Factor From the Carotid Artery , 1994, Stroke.

[7]  J. Erusalimsky,et al.  Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells. Synergistic interaction with hypoxia. , 1995, Circulation.

[8]  J. Isner,et al.  Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[9]  S. Swain,et al.  Antigen-independent changes in naive CD4 T cells with aging , 1996, The Journal of experimental medicine.

[10]  D. Donner,et al.  Induction of Vascular Endothelial Growth Factor by Insulin-like Growth Factor 1 in Colorectal Carcinoma* , 1996, The Journal of Biological Chemistry.

[11]  J. Isner,et al.  Vascular endothelial growth factor/vascular permeability factor augments nitric oxide release from quiescent rabbit and human vascular endothelium. , 1997, Circulation.

[12]  J. Isner,et al.  Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. , 1998, Circulation.

[13]  Takayuki Asahara,et al.  Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb , 1996, The Lancet.

[14]  S. Epstein,et al.  Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. , 1994, Circulation.

[15]  T. Maciag,et al.  FGF-1-dependent proliferative and migratory responses are impaired in senescent human umbilical vein endothelial cells and correlate with the inability to signal tyrosine phosphorylation of fibroblast growth factor receptor-1 substrates , 1996, The Journal of cell biology.

[16]  J. Isner,et al.  Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries. , 1997, The American journal of pathology.

[17]  S. Soker,et al.  Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. , 1995, Cancer research.

[18]  E. Brogi,et al.  Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. , 1994, The Journal of clinical investigation.

[19]  P. Pietschmann,et al.  The Effect of Age on the Transendothelial Migration of Human T Lymphocytes , 1996, Scandinavian journal of immunology.

[20]  Peipei Ping,et al.  Intracoronary gene transfer of fibroblast growth factor–5 increases blood flow and contractile function in an ischemic region of the heart , 1996, Nature Medicine.

[21]  StefanoTaddei,et al.  Aging and Endothelial Function in Normotensive Subjects and Patients With Essential Hypertension , 1995 .

[22]  J. Greenwood,et al.  Factors controlling T-cell migration across rat cerebral endothelium in vitro , 1997, Journal of Neuroimmunology.

[23]  W. Ershler,et al.  Effect of host age on tumor-associated angiogenesis in mice. , 1990, Journal of the National Cancer Institute.

[24]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[25]  L. Fried,et al.  Epidemiology of aging. , 2000, Epidemiologic reviews.

[26]  M. Creager,et al.  Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. , 1996, Hypertension.

[27]  Richard A. Miller The Aging Immune System: Primer and Prospectus , 1996, Science.

[28]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[29]  A. Passaniti,et al.  Altered angiogenesis underlying age-dependent changes in tumor growth. , 1994, Journal of the National Cancer Institute.

[30]  J. Garb,et al.  Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic fibroblast growth factor in a rabbit model of acute lower limb ischemia: dose-response effect of basic fibroblast growth factor. , 1992, Journal of vascular surgery.

[31]  R. Ogilvie,et al.  Basic fibroblast growth factor increases collateral blood flow in rats with femoral arterial ligation. , 1996, Circulation research.

[32]  T. Lüscher,et al.  Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery. , 1996, The Journal of clinical investigation.

[33]  G. D. Phillips,et al.  PDGF-BB induced chemotaxis is impaired in aged capillary endothelial cells , 1994, Mechanisms of Ageing and Development.

[34]  Atsushi Namiki,et al.  Indirect Angiogenic Cytokines Upregulate VEGF and bFGF Gene Expression in Vascular Smooth Muscle Cells, Whereas Hypoxia Upregulates VEGF Expression Only , 1994 .

[35]  R. Thompson,et al.  Mechanisms of angiogenesis. , 1987, Annual review of physiology.

[36]  D. Karnofsky Neoplastic diseases. , 1952, Annual review of medicine.

[37]  J. Isner,et al.  Mouse model of angiogenesis. , 1998, The American journal of pathology.

[38]  G. Haines,et al.  Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. , 1994, Journal of immunology.

[39]  S. Weisbroth CHAPTER 14 – Neoplastic Diseases , 1974 .

[40]  E. Brogi,et al.  Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. , 1994, Circulation.

[41]  L. Aiello,et al.  Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. , 1994, The New England journal of medicine.