Molecular and Cellular Mechanisms of Angiogenesis

Abstract ADMA (asymmetric dimethylarginine) is a cardiovascular risk factor and an endogenous inhibitor of NOS (nitric oxide synthase). ADMA is metabolized by DDAHs (dimethylarginine dimethylaminohydrolases). ADMA levels are increased in cardiovascular disorders associated with abnormal angiogenesis but the mechanisms are poorly understood. Recent studies show that altering ADMA metabolism in vivo and in vitro modulates the activity of Rho GTPases, key regulators of actin dynamics, endothelial cell motility and angiogenesis. In the present review, we consider this and other NO-dependent and -independent molecular mechanisms by which the DDAH/ADMA pathway regulates angiogenesis. ADMA (asymmetric dimethylarginine) metabolism and clearance ADMA is a cardiovascular risk factor and its plasma and tissue levels are increased in disorders associated with dysregulated angiogenesis, including hypertension, atherosclerosis, diabetes, insulin resistance, hypercholesterolaemia and homo- The DDAH/ADMA pathway in angiogenesis The significance of the DDAH/ADMA pathway in angiogenesis has been demonstrated in a number of systems. Homozygous deletion of DDAH I in mice is lethal, whereas HT (heterozygous) deletion of the gene results in endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure Mechanisms by which DDAH/ADMA regulates angiogenesis Angiogenesis depends on the activation, migration and proliferation of endothelial cells under the regulatory control of growth factors such as VEGF (vascular endothelial growt