DISTINCT ROLES FOR Cx37 AND Cx40 IN REGULATING VASCULAR RESPONSES FOLLOWING ISCHEMIA

Abstract

Gap junctions are intercellular channels that permit passage of electrical and chemical signals between neighbouring cells. Vascular endothelium typically co-expresses Cx37 and Cx40, but may downregulate its expression of Cx37 (and upregulate Cx43) in response to changes in flow. The specific regulatory roles mediated by vascular endothelial connexins, and the consequences of altered connexin expression, remain unclear. In this study, we hypothesized that Cx37 and Cx40 regulate distinct vascular responses. We further hypothesize that Cx37 is predominantly involved in vascular growth control, whereas vascular growth is not affected by ablation of Cx40 expression. We show herein that Cx37, but not Cx40 or Cx43, suppresses growth of a highly-proliferative cancer cell line by inducing G1 cell cycle accumulation. We further show that Cx37-deficient mice, lacking Cx37's putative growth inhibitory effect on the vasculature, exhibit a more extensive native and post-ischemic collateral circulation, and greater ischemia-induced microvascular density. In addition, Cx37-/- mice demonstrate a functional improvement in recovery over wild-type animals in two models of hindlimb ischemia. By contrast, Cx40-/- mice fail to recover distal limb flow following unilateral hindlimb ischemia, resulting in necrosis. Long-term angiotensin II antagonism normalized post-ischemic hindlimb bloodflow, reduced macrophage infiltration, and delayed (but did not reverse) the necrotic phenotype of these animals. In summary, we show a distinct role for each of the endothelial connexins, Cx37 and Cx40, in regulating post-ischemic vascular responses.