Defining Endothelial Cell-Derived Factors That Promote Pericyte Recruitment and Capillary Network Assembly.
Defining Endothelial Cell-Derived Factors That Promote Pericyte Recruitment and Capillary Network Assembly.
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DOI：
10.1161/atvbaha.120.314948
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Davis GE
中科院分区：
文献类型：
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作者：
Kemp SS;Aguera KN;Cha B;Davis GE
我们试图识别和研究在毛细血管网络形成过程中控制周细胞向EC管募集和周细胞诱导的管成熟的主要内皮细胞衍生因子的功能作用。我们确定血小板衍生生长因子-BB、血小板衍生生长因子-DD、内皮素(ET-1)、转化生长因子β、S和血红蛋白-表皮生长因子是内皮细胞周细胞聚集的关键单项和联合调节因子。利用新的仅检测周细胞的方法，我们证明PDGF-BB、PDGF-DD和ET-1是周细胞侵袭的主要直接驱动因素。它们与周细胞的结合可诱导侵袭，就好像内皮细胞存在一样。而转化生长因子βS和HB-EGF直接刺激周细胞侵袭的能力较弱。相反，转化生长因子β1可以作为周细胞的上游引物，刺激PDGFs和ET-1的侵袭。HB-EGF与PDGFs和ET-1一起刺激周细胞增殖。使用EC-周细胞共培养，分别使用中和抗体或化学抑制剂单独或联合阻断这些EC衍生因子或其周细胞受体，干扰周细胞的募集和增殖。作为个体因素，PDGF-BB和ET-1对这些事件的影响最大。然而，当阻断试剂联合干扰上述每一种因子或其受体时，对周细胞的募集、增殖和周细胞诱导的基底膜沉积发生了更戏剧性和更深刻的阻断。在这种情况下，内皮细胞形成的管子变得更宽、更小，就像没有周细胞一样。总体而言，这些新的研究定义和表征了关键的EC衍生因子在毛细血管网络组装过程中控制周细胞招募、增殖和周细胞诱导的基底膜沉积的功能作用。
We sought to identify and investigate the functional role of the major endothelial cell (EC)-derived factors that control pericyte recruitment to EC tubes and pericyte-induced tube maturation during capillary network formation. We identify PDGF-BB, PDGF-DD, endothelin (ET-1), TGFβs, and HB-EGF, as the key individual and combined regulators of pericyte assembly around EC tubes. Using novel pericyte only assays, we demonstrate that PDGF-BB, PDGF-DD, and ET-1 are the primary direct drivers of pericyte invasion. Their addition to pericytes induces invasion as if ECs were present. In contrast, TGFβs and HB-EGF, have minimal ability to directly stimulate pericyte invasion. In contrast, TGFβ1 can act as an upstream pericyte primer to stimulate invasion in response to PDGFs and ET-1. HB-EGF stimulates pericyte proliferation along with PDGFs and ET-1. Using EC-pericyte co-cultures, individual or combined blockade of these EC-derived factors, or their pericyte receptors, using neutralizing antibodies or chemical inhibitors, respectively, interferes with pericyte recruitment and proliferation. As individual factors, PDGF-BB and ET-1 have the strongest impact on these events. However, when the blocking reagents are combined to interfere with each of the above factors or their receptors, more dramatic and profound blockade of pericyte recruitment, proliferation and pericyte-induced basement membrane deposition occurs. Under these conditions, ECs form tubes that become much wider and less elongated as if pericytes were absent. Overall, these new studies define and characterize a functional role for key EC-derived factors controlling pericyte recruitment, proliferation, and pericyte-induced basement membrane deposition during capillary network assembly.