Requirement Of Beta 1 Integrin For Endothelium-Dependent Vasodilation And Collateral Formation In Hindlimb Ischemia

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 beta 1 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 beta 1 integrin-blocking antibody or tamoxifen-induced endothelial cell-specific deletion of the gene for beta 1 integrin (Itgb1) inhibited both arteriogenesis and angiogenesis. Using high frequency ultrasound, we demonstrated that beta 1 integrin-blocking antibody or endothelial cell-specific depletion of beta 1 integrin attenuated FMD of the femoral artery, and blocking of beta 1 integrin function did not further decrease FMD in eNOS-deficient mice. Our data suggest that endothelial beta 1 integrin is required for both acute and chronic widening of the arterial lumen in response to hindlimb ischemia, potentially via functional interaction with eNOS.