Requirement of ß1 integrin for endothelium-dependent vasodilation and collateral formation in hindlimb ischemia.

ABSTRACT

An acute increase in blood flow triggers flow-mediated dilation (FMD), which is mainly mediated by endothelial nitric oxide synthase (eNOS). A long-term increase in blood flow chronically enlarges the arterial lumen, a process called arteriogenesis. In several common human diseases, these processes are disrupted for as yet unknown reasons. Here, we asked whether ß1 integrin, a mechanosensory protein in endothelial cells, is required for FMD and arteriogenesis in the ischemic hindlimb. Permanent ligation of the femoral artery in C57BL/6 J mice enlarged pre-existing collateral arteries and increased numbers of arterioles in the thigh. In the lower leg, the numbers of capillaries increased. Notably, injection of ß1 integrin-blocking antibody or tamoxifen-induced endothelial cell-specific deletion of the gene for ß1 integrin (Itgb1) inhibited both arteriogenesis and angiogenesis. Using high frequency ultrasound, we demonstrated that ß1 integrin-blocking antibody or endothelial cell-specific depletion of ß1 integrin attenuated FMD of the femoral artery, and blocking of ß1 integrin function did not further decrease FMD in eNOS-deficient mice. Our data suggest that endothelial ß1 integrin is required for both acute and chronic widening of the arterial lumen in response to hindlimb ischemia, potentially via functional interaction with eNOS.