Requirement of \u03b21 integrin for endothelium-dependent vasodilation and collateral formation in hindlimb ischemia

Carina Henning,Christian Heiss,Anna Branopolski,Ferdinand Le Noble,Roberto Sansone,Eckhard Lammert,Malte Kelm,Jelle Ludolf Postma,Christopher Nicolaus,Daniel Eberhard,Patrik Huelsemann,Dominik Schuler,Dimitrios Dimitroulis

doi:10.1038/s41598-019-53137-x

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 β1 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 β1 integrin-blocking antibody or tamoxifen-induced endothelial cell-specific deletion of the gene for β1 integrin (Itgb1) inhibited both arteriogenesis and angiogenesis. Using high frequency ultrasound, we demonstrated that β1 integrin-blocking antibody or endothelial cell-specific depletion of β1 integrin attenuated FMD of the femoral artery, and blocking of β1 integrin function did not further decrease FMD in eNOS-deficient mice. Our data suggest that endothelial β1 integrin is required for both acute and chronic widening of the arterial lumen in response to hindlimb ischemia, potentially via functional interaction with eNOS.

Highlights

An acute increase in blood flow triggers flow-mediated dilation (FMD), which is mainly mediated by endothelial nitric oxide synthase
Endothelial β1 integrin expression increased in the calf, while only showing a small trend towards higher expression in the thigh (Supplementary Fig. S3), consistent with a previous report showing that hypoxia via HIF-1α can induce β1 integrin expression[29]
Our present data show that endothelial β1 integrin is required for induction of FMD in response to acute increases in blood flow and for arteriogenesis caused by chronically increased blood flow after femoral artery (FA) ligation

Summary

Introduction

An acute increase in blood flow triggers flow-mediated dilation (FMD), which is mainly mediated by endothelial nitric oxide synthase (eNOS). While the mechanisms are unknown, this structural adaptation involves the outward remodelling along with proliferation of endothelial cells and vascular smooth muscle cells (SMC), monocyte recruitment, and extracellular matrix turnover[4] The latter processes result in larger vascular lumens and increased numbers of arterioles and capillaries[1], allowing more blood to flow through the skeletal muscles of the limbs, alleviating hypoxia in situations of increased demand for oxygen and nutrients[1]. Β1 integrin appears to be essential for blood vessel formation during embryonic development as well as for postnatal vascular remodelling, smooth muscle vasomotor control, and wound healing[22,23,24] It regulates endothelial cell polarity and arteriolar lumen formation[25]. We provide evidence that β1 integrin plays an important role in both FMD and arteriogenesis in the thigh during hindlimb ischemia (HI)

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Results

Conclusion