Clinical and Genetic Correlates of Circulating Angiopoietin-2 and Soluble Tie-2 in the Community

Background—Experimental studies suggest that endothelial growth factors play an important role in angiogenesis and vascular remodeling. The clinical and genetic correlates of circulating angiopoietin-2 (Ang-2) and its soluble receptor/regulator Tie-2 (sTie-2) have not been determined in a community-based sample. Methods and Results—Serum Ang-2 and sTie-2 were assayed in 3778 third-generation cohort participants of the Framingham Heart Study (mean age, 40±9 years; 53% women). Clinical correlates and heritability of both biomarkers were assessed using generalized estimating equations and variance-component analyses. Ang-2 levels were higher and sTie-2 levels were lower in women than in men. Ang-2 was positively related to age, smoking, systolic blood pressure, hypertension treatment, and diabetes (P<0.05 for all) but was inversely associated with total cholesterol and diastolic blood pressure (P<0.0001 for both), and sTie-2 was positively associated with body mass index, diabetes, and triglycerides but was inversely related to age, alcohol consumption, and glomerular filtration rate (P<0.05 for all). Both Ang-2 and sTie-2 were higher in participants with metabolic syndrome (P<0.005), with stronger associations of Ang-2 with blood pressure traits and of sTie-2 with obesity-dyslipidemia components. Heritability estimates for Ang-2 and sTie-2 were 27% and 56%, respectively (P<0.0001). A region on chromosome 9 was significantly linked to circulating sTie-2 levels (logarithm of the odds score, 8.31). Conclusion—Circulating levels of Ang-2 and sTie-2 are heritable traits associated with cardiovascular disease risk factors, including the metabolic syndrome. These observations are consistent with the notion that angiogenesis and vascular remodeling are determined in part by genetic influences and associated with metabolic risk factors.

[1]  B. Lowell,et al.  Adipose tissue mass can be regulated through the vasculature , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Cahill,et al.  Ethanol stimulates endothelial cell angiogenic activity via a Notch- and angiopoietin-1-dependent pathway. , 2008, Cardiovascular research.

[3]  S. Hussain,et al.  Regulation of angiopoietin and Tie-2 receptor expression in non-reproductive tissues by estrogen , 2002, Steroids.

[4]  G. Gibbons,et al.  The emerging concept of vascular remodeling. , 1994, The New England journal of medicine.

[5]  G. Lip,et al.  Plasma Angiopoietin-1, Angiopoietin-2, Angiopoietin Receptor Tie-2, and Vascular Endothelial Growth Factor Levels in Acute Coronary Syndromes , 2004, Circulation.

[6]  P. Oostveldt,et al.  Reference values and basic determinants of telomere length in a large middle-aged population , 2006 .

[7]  M. Carrier,et al.  Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers. , 2008, Canadian journal of physiology and pharmacology.

[8]  Thomas N. Sato,et al.  Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation , 1995, Nature.

[9]  Yihai Cao.  Angiogenesis modulates adipogenesis and obesity. , 2007, The Journal of clinical investigation.

[10]  G. Lip,et al.  Abnormal angiopoietins 1&2, angiopoietin receptor Tie‐2 and vascular endothelial growth factor levels in hypertension: relationship to target organ damage [a sub‐study of the Anglo‐Scandinavian Cardiac Outcomes Trial (ASCOT)] , 2005, Journal of internal medicine.

[11]  G. Lip,et al.  Angiopoietin‐2 levels as a biomarker of cardiovascular risk in patients with hypertension , 2008, Annals of medicine.

[12]  S. Papson,et al.  “Model” , 1981 .

[13]  G. Lip,et al.  Plasma angiopoietin-1, angiopoietin-2, and angiopoietin receptor tie-2 levels in congestive heart failure. , 2004, Journal of the American College of Cardiology.

[14]  S. Vatner,et al.  A Redox-Dependent Pathway for Regulating Class II HDACs and Cardiac Hypertrophy , 2008, Cell.

[15]  G. Lip,et al.  Plasma vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in diabetes: implications for cardiovascular risk and effects of multifactorial intervention. , 2004, Diabetes care.

[16]  B. Olsen,et al.  Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. , 2006, Experimental cell research.

[17]  H. Augustin,et al.  Angiopoietins: a link between angiogenesis and inflammation. , 2006, Trends in immunology.

[18]  G. Koh,et al.  Angiopoietin-1 Reduces VEGF-Stimulated Leukocyte Adhesion to Endothelial Cells by Reducing ICAM-1, VCAM-1, and E-Selectin Expression , 2001, Circulation research.

[19]  Renee Dickie,et al.  The FASEB Journal • Research Communication Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy , 2022 .

[20]  E. Benjamin,et al.  Vascular endothelial growth factor, its soluble receptor, and hepatocyte growth factor: clinical and genetic correlates and association with vascular function. , 2009, European heart journal.

[21]  S. Harper,et al.  Human podocytes express angiopoietin 1, a potential regulator of glomerular vascular endothelial growth factor. , 2002, Journal of the American Society of Nephrology : JASN.

[22]  Qiong Yang,et al.  The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. , 2007, American journal of epidemiology.

[23]  L. Udoff,et al.  Effect of estrogen on angiogenesis in co-cultures of human endometrial cells and microvascular endothelial cells. , 2003, Human reproduction.

[24]  H. Augustin,et al.  Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation , 2006, Nature Medicine.

[25]  J. Isner,et al.  Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. , 1998, Circulation research.

[26]  Takahiko Nakagawa,et al.  Hypokalemic nephropathy is associated with impaired angiogenesis. , 2008, Journal of the American Society of Nephrology : JASN.

[27]  P. Sucharda,et al.  Angiogenic factors are elevated in overweight and obese individuals , 2005, International Journal of Obesity.

[28]  G. Martiny-Baron,et al.  Identification of a soluble form of the angiopoietin receptor TIE-2 released from endothelial cells and present in human blood , 2004, Angiogenesis.

[29]  L. McCullough,et al.  Estradiol Regulates Angiopoietin-1 mRNA Expression Through Estrogen Receptor-&agr; in a Rodent Experimental Stroke Model , 2005, Stroke.

[30]  K. Alitalo,et al.  Angiopoietin-1 Protects Against the Development of Cardiac Allograft Arteriosclerosis , 2003, Circulation.

[31]  D. Dumont,et al.  The angiopoietins and Tie2/Tek: adding to the complexity of cardiovascular development. , 2002, Seminars in cell & developmental biology.

[32]  M. Fujita,et al.  Abstract 3945: Soluble Flk-1 and Soluble Tie-2, Endogenous Inhibitors of Endothelial Cell-specific Angiogenic Signals, are Increased in Serum of Patients with Metabolic Syndrome. , 2006 .

[33]  M. Boulton,et al.  The angiopoietin/Tie-2 system regulates pericyte survival and recruitment in diabetic retinopathy. , 2008, Investigative ophthalmology & visual science.

[34]  G. Lip,et al.  Circulating biomarkers of angiogenesis as indicators of left ventricular systolic dysfunction amongst patients with coronary artery disease , 2009, Journal of internal medicine.

[35]  S. Yagihashi,et al.  Expression of retinoic acid-inducible gene-I (RIG-I) in macrophages: possible involvement of RIG-I in atherosclerosis. , 2007, Journal of atherosclerosis and thrombosis.

[36]  G. Lip,et al.  Angiopoietin-1 and angiopoietin-2 in diabetes mellitus: relationship to VEGF, glycaemic control, endothelial damage/dysfunction and atherosclerosis. , 2005, Atherosclerosis.

[37]  R. Khalil.  Sex hormones as potential modulators of vascular function in hypertension. , 2005, Hypertension.

[38]  J. LaManna,et al.  Cerebral angiogenic factors, angiogenesis, and physiological response to chronic hypoxia differ among four commonly used mouse strains. , 2007, Journal of applied physiology.

[39]  C. Vio,et al.  Ischemic acute renal failure induces the expression of a wide range of nephrogenic proteins. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[40]  K. Peters.  Vascular endothelial growth factor and the angiopoietins: working together to build a better blood vessel. , 1998, Circulation research.

[41]  R. G. Mitchell,et al.  Plasma levels of soluble Tie2 and vascular endothelial growth factor distinguish critical limb ischemia from intermittent claudication in patients with peripheral arterial disease. , 2008, Journal of the American College of Cardiology.

[42]  J. C. Christiansen,et al.  Determinants of sensitivity and specificity of electrocardiographic criteria for left ventricular hypertrophy. , 1990, Circulation.

[43]  F. le Noble,et al.  Angiogenesis and hypertension , 1998, Journal of hypertension.

[44]  R. Lijnen,et al.  Modulation of angiogenesis during adipose tissue development in murine models of obesity. , 2005, Endocrinology.

[45]  Fernando Costa,et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. , 2006, Current opinion in cardiology.

[46]  Y. Suh,et al.  Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor , 2008, Cardiovascular research.