Role of Egfl7 in Angiogenesis and Vascular Injury

描述（由申请人提供）：血管生成对于脊椎动物胚胎功能循环系统的发育至关重要。这些过程的核心是内皮细胞（EC），它们在血管内壁形成一个连续的层，并构成一个响应环境刺激而变化的动态系统。表皮生长因子样7 （EGFL7）由EC表达，以可溶性和ecm结合的形式存在，可能以自分泌和旁分泌的方式起作用。成人血管内皮表达水平低，在生理性和病理性血管生成过程中被诱导表达。我们之前已经证明，Egfl7是胚胎发育和视网膜出生后血管生成过程中血管生成的关键促血管生成调节剂。Egfl7信号转导的机制尚不清楚。然而，我们的研究表明，在体内，EGFL7与内皮Notch相互作用并调节Notch细胞内信号传导。其在微血管损伤和修复中的作用尚不清楚。骨髓（BM）血管系统是解决这些问题的理想模型，因为可以在一个定义良好的环境中研究血管壁龛中窦内皮和HSPC的损伤和再生。重要的是，该模型与病理性血管生成有关，即组织损伤，缺血和肿瘤血管生成。该建议的一个中心假设是EGFL7在脑基血管损伤时起作用，促进内皮和造血再生，从而恢复受损组织。我们进一步提出，EGFL7通过自分泌机制，通过与VEGF和Notch的串扰，促进血管损伤后的新生血管生成；EGFL7通过旁分泌机制，作为一种“血管分泌因子”，在基底动脉血管壁龛中由正弦波EC分泌，促进造血。我们将在三个具体目标中检验这些假设。首先，我们将确定Egfl7在BM血管生态位中的作用。其次，我们将研究Egfl7信号在原发性人EC中的分子和生化基础。第三，我们将确定EGFL7信号在BM血管生态位中的作用机制。内皮细胞构成了一个动态系统，它会对环境刺激做出反应，包括微血管的损伤。了解这些过程是如何在生物体中进行的，可能会导致内皮细胞帮助修复受损血管或限制肿瘤血液供应的治疗方法。

DESCRIPTION (provided by applicant): Angiogenesis is crucial for the development of a functional circulatory system in the vertebrate embryo. Central to these processes are the endothelial cells (EC) that form a continuous layer lining the blood vessels and constitute a dynamic system that changes in response to environmental stimuli. Epidermal growth factor-like 7 (EGFL7) is expressed by EC and is present both in soluble of ECM-bound forms and may act both in an autocrine and paracrine manner. Expression in adult endothelium is low but becomes induced during physiological and pathological angiogenesis. We have previously shown that Egfl7 is a critical, pro-angiogenic regulator of angiogenesis during embryonic development and in during post-natal angiogenesis in the retina. The mechanisms by which Egfl7 signals are transduced are not well understood. However, our studies show in vivo, that EGFL7 interacts with endothelial Notch and modulates Notch intracellular signaling. Little is known about its role in response to microvascular injury and repair. The bone marrow (BM) vasculature is an ideal model to address these questions because injury and regeneration of the sinusoidal endothelium and the HSPC residing in the vascular niche can be studied in a well-defined setting. Importantly, this model is relevant for pathological angiogenesis i.e. during tissue damage, ischemia, and tumor angiogenesis. A central hypothesis of this proposal is that EGFL7 acts in response to injury of the BM vasculature to promote endothelial and hematopoietic regeneration that restores the damaged tissue. We further propose that EGFL7 acts through an autocrine mechanism to promote neoangiogenesis in response to vascular injury via cross-talk with VEGF and Notch, and that EGFL7 acts through a paracrine mechanism as an "angiocrine factor" secreted by sinusoidal EC in the BM vascular niche to promote hematopoiesis. We will test these hypotheses in three specific aims. First, we will determine the role of Egfl7 in the BM vascular niche. Second, we will investigate the molecular and biochemical basis of Egfl7 signaling in primary human EC. Third, we will identify mechanisms of EGFL7 signaling in the BM vascular niche. Endothelial cells constitute a dynamic system that changes in response to environmental stimuli, including injury of the microvasculature. Understanding how these processes are orchestrated in a living organism may lead to treatments in which endothelial cells aid the repair of damaged vessels or restrict the blood supply of tumors.