Stroke is one of the most devastating manifestations of two common diseases, atherosclerosis and hypertension. It represents the second leading cause of death and a major cause of disability worldwide. Besides age (a nonmodifiable risk factor), hypertension is the most important cardiovascular risk factor for developing both ischemic and hemorrhagic stroke, as well as small vessel disease predisposing to lacunar infarction, white matter lesions, and cerebral microbleeds. In addition, hypertension predisposes to atherosclerosis and cardiac diseases (notably atrial fibrillation), thereby promoting cerebral embolism. Inflammatory mechanisms play a central role in the pathogenesis and progression of atherosclerosis, plaque rupture, thrombosis, and stroke. Endothelial dysfunction, in part resulting from excessive production of reactive oxygen species, is an important mechanism of cerebrovascular damage. This article reviews recent data on vascular mechanisms that participate in the pathogenesis of stroke.

The hallmarks of insulin action are the stimulation and suppression of anabolic and catabolic responses, respectively. These responses are orchestrated by the insulin pathway and are initiated by the binding of insulin to the insulin receptor, which leads to activation of the receptor's intrinsic tyrosine kinase. Severe defects in the insulin pathway, such as in types A and B and advanced type 1 and 2 diabetes lead to severe insulin resistance, resulting in a partial or complete absence of response to exogenous insulin and other known classes of antidiabetes therapies. We have characterized a novel class of arylalkylamine vanadium salts that exert potent insulin-mimetic effects downstream of the insulin receptor in adipocytes. These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. Administration of these compounds to animal models of diabetes lowered glycemia and normalized the plasma lipid profile. Arylalkylamine vanadium compounds also showed antidiabetic effects in severely diabetic rats with undetectable circulating insulin. These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. This represents a novel therapeutic approach for diabetic patients with severe insulin resistance. Diabetes 56: 486 -493, 2007