Abstract
Background/Aims:Shear stress plays major roles in developmental angiogenesis, particularly in blood vessel remodeling and maturation but little is known about the shear stress sensors involved in this process. Our recent study identified endothelial Kir2.1 channels as major contributors to flow-induced vasodilation, a hallmark of the endothelial flow response. The goal of this study is to establish the role of Kir2.1 in the regulation of retinal angiogenesis.Methods:The retina of newly born Kir2.1+/− mice were used to investigate the sprouting angiogenesis and remodeling of newly formed branched vessels. The structure, blood density and mural cell coverage have been evaluated by immunohistochemistry of the whole-mount retina. Endothelial cell alignment was assessed using CD31 staining. The experiments with flow-induced vasodilation were used to study the cerebrovascular response to flow.Results:Using Kir2.1-deficient mice, we show that the retinas of Kir2.1+/− mice have higher vessel density, increased lengths and increased number of the branching points, as compared to WT littermates. In contrast, the coverage by αSMA is decreased in Kir2.1+/− mice while pericyte coverage does not change. Furthermore, to determine whether deficiency of Kir2.1 affects vessel pruning, we discriminated between intact and degraded vessels or “empty matrix sleeves” and found a significant reduction in the number of empty sleeves on the peripheral part of the retina or “angiogenic front” in Kir2.1+/− mice. We also show that Kir2.1 deficiency results in decreased endothelial alignment in retinal endothelium and impaired flow-induced vasodilation of cerebral arteries, verifying the involvement of Kir2.1 in shear-stress sensing in retina and cerebral circulation.Conclusion:This study shows that shear-stress sensitive Kir2.1 channels play an important role in pruning of excess vessels and vascular remodeling during retinal angiogenesis. We propose that Kir2.1 mediates the effect of shear stress on vessel maturation.
Highlights
The formation of a functional network of blood vessels is essential for vertebrate development and organ function
Several studies showed that one of the important remodeling factors in developmental angiogenesis is shear stress, a frictional force generated by blood flow, that is known to play a major role in vascular remodeling in general [5]
In order to determine if Kir2.1 channels regulate retinal angiogenesis, we examined the structure and density of blood vessel networks in retinas of new born Kir2.1+/mice
Summary
The formation of a functional network of blood vessels is essential for vertebrate development and organ function. New blood vessel formation is called angiogenesis and consists of two major phases: first is sprouting, the process of forming new vessels to create a meshwork of branched capillaries, and remodeling, the process of removal or pruning of redundant vessels to form a mature plexus and to increase the efficiency of the perfused network [1, 2]. Franco et al [8] demonstrated that regression of blood vessels in mouse retina results from flow-sensitive migration of endothelial cells from vessels with low flow to vessels with higher flow and results in the maturation of the plexus It is important, to understand the mechanisms that might couple between shear stress and developmental vascular regression
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