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中功能循环系统的发展至关重要。这些过程的中心是内皮细胞(EC)，它形成了一层连续的血管衬里，并构成了一个动态系统，随着环境刺激的变化而变化。表皮生长因子样7(EGFL7)由内皮细胞表达，以细胞外基质结合的形式存在，既可自分泌又可旁分泌。成体内皮细胞低表达，但在生理性和病理性血管生成过程中被诱导表达。我们先前已经证明，Egfl7在胚胎发育和出生后视网膜血管生成过程中是一个关键的促血管生成调节因子。Egfl7信号转导的机制还不是很清楚。然而，我们的研究表明，在体内，EGFL7与内皮细胞Notch相互作用，并调节Notch细胞内信号。对其在微血管损伤和修复中的作用知之甚少。骨髓(BM)血管系统是解决这些问题的理想模型，因为可以在明确的环境下研究血管壁龛内窦内皮细胞和HSPC的损伤和再生。重要的是，这个模型与病理性血管生成有关，即在组织损伤、缺血和肿瘤血管生成期间。这一建议的一个中心假设是，EGFL7对骨髓血管系统的损伤做出反应，促进内皮和造血再生，修复受损的组织。我们进一步认为，EGFL7通过与血管内皮生长因子和Notch的串扰，通过自分泌机制促进新生血管生成，并通过旁分泌机制发挥作用，由BM血管内皮细胞分泌的“血管分泌因子”促进造血。我们将在三个具体目标上检验这些假设。首先，我们将确定Egfl7在BM血管生态位中的作用。其次，我们将研究原代人类EC中Egfl7信号转导的分子和生化基础。第三，我们将确定EGFL7信号在BM血管壁龛中的机制。内皮细胞构成了一个动态系统，它会随着环境刺激，包括微血管系统的损伤而发生变化。了解这些过程是如何在活的有机体中协调的，可能会导致内皮细胞帮助修复受损的血管或限制肿瘤的血液供应的治疗。

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.