Shear Stress and VE-Cadherin: The Molecular Mechanism of Vascular Fusion
Shear Stress and VE-Cadherin: The Molecular Mechanism of Vascular Fusion
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DOI：
10.1161/atvbaha.118.310823
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发表时间：
2018-09-01
影响因子：
8.7
通讯作者：
Jones, Elizabeth A. V.
中科院分区：
文献类型：
--
作者：
Caolo, Vincenza;Peacock, Hanna M.;Jones, Elizabeth A. V.
目的血管融合是发育过程中血管扩张的重要机制，但其在出生后血管扩张中的意义尚不清楚。在融合过程中，2条相邻血管合并，共享1个较大的管腔。本研究的目的是确定负责血管fusion.Approach和结果的分子机制，我们以前表明，低剪切应力和DAPT（N-[N-（3，5-difluorophenacetyl）-L-丙氨酰]-S-苯基甘氨酸叔丁酯）在胚胎治疗的结果在一个hyperperfused血管丛，增加剪切应力水平可以防止DAPT诱导的融合。因此，我们研究了血管内皮钙粘蛋白（VEC）磷酸化，因为这是低切应力和DAPT治疗的常见下游靶点。DAPT处理和剪切应力降低后VEC磷酸化增加。增加的磷酸化独立于Notch细胞内结构域的切割而发生。增加剪切应力通过DAPT处理通过引起磷酸酶血管内皮蛋白酪氨酸磷酸酶与VEC的缔合，抵消VEC磷酸化来挽救过度融合。最后，Src（原癌基因酪氨酸蛋白激酶Src）抑制阻止内皮细胞中的VEC磷酸化，并可以挽救低剪切应力和DAPT治疗诱导的过度融合。Moesin，一个VEC的目标，是以前报道介导的内皮细胞重排过程中lumenization，relocalizes细胞膜在血管床hyperfusion.Conclusions这项研究提供了第一个证据表明，VEC磷酸化，诱导DAPT治疗和低剪切应力，参与血管重塑过程中的融合。
Objective Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion.Approach and Results We previously showed that both low shear stress and DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion.Conclusions This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.