Abstract 390: Cardiovascular Risk Factors and Endothelial Dysfunction Cause Rarefaction of the Collateral Circulation and Impaired Recovery from Ischemia

Abstract

Listen

Translate article

Aging and cardiovascular risk factors (CVRF) such as diabetes, hypertension, dyslipidemia and metabolic syndrome have been associated with collateral insufficiency in animals and humans. Long-standing CVRF as well as collateral insufficiency associate with poorer outcomes following acute ischemic stroke or myocardial infarction. Evidence suggests that endothelial dysfunction (decreased eNOS activity and NO bioavailability) is caused by and contributes to CVRF, and promotes atherosclerosis and thrombosis in patients with CVRF. Aging and eNOS deficiency have been shown to cause rarefaction of native (pre-existing) cerebral and hindlimb collaterals in mice and to reduce collateral remodeling in response to arterial occlusion. To determine whether endothelial dysfunction and CVRF cause collateral rarefaction and/or impair remodeling, we examined recovery of perfusion following femoral artery ligation (FAL) and native cerebral pial collateral extent (density and diameter) in the following mouse models (all 7-8 mos-age): chronic L-NAME treatment (endothelial dysfunction), ob/ob (obesity), LDLR -/- on high-fat diet (hyperlipidemia), LDLR -/- ; ob/ob (metabolic syndrome), RenTgMK +/- (hypertension), and Akita (type-1 diabetes). Hindlimb perfusion immediately after FAL (dependent on native collateral extent) and recovery over 21 days (dependent on collateral remodeling) were impaired by chronic endothelial dysfunction, hypertension, metabolic syndrome, and diabetes (p<0.05) but not by obesity and hyperlipidemia. Similarly, native pial collateral extent was significantly reduced in models of endothelial dysfunction, hypertension, metabolic syndrome and diabetes. The functional significance of CVRF-induced collateral rarefaction was evident as more severe ischemic injury and use impairment in hindlimb and larger infarction in brain after middle cerebral artery occlusion. Investigations into the mechanisms of CVRF-induced collateral rarefaction and treatments to prevent it are ongoing. These data show that CVRF not only impair collateral remodeling but also cause significant loss of native collaterals, resulting in worse ischemic tissue injury after acute obstruction and fewer collaterals available for remodeling.