SPARC AS A REGULATOR OF VEGF ACTIVITY

血管生成是从已有的血管发展出新的血管系统，在许多生理过程和病理事件中起着关键作用。对组织中血管生成如何调节的更多理解将有助于各种生物和医学领域。细胞外基质（ECM）和在ECM中发现的基质细胞蛋白通过它们与控制血管发育的内皮细胞和血管生成因子的相互作用而作为血管生成的重要调节剂起作用。血管内皮生长因子（vascular endothelial growth factor，VEGF）是一种分泌性蛋白质，是一种酸性的富含半胱氨酸的蛋白质，近年来发现它与VEGF相互作用并调节VEGF的活性，而VEGF是正常和病理状态下血管生成的主要刺激因子。了解ECM中与VEGF相互作用的蛋白质及其调节VEGF活性的能力将有助于我们了解VEGF诱导的血管生成及其在组织稳态和病理学中的作用。在本申请中，我将进一步表征VEGF和VEGF的相互作用。将测定VEGF阻断VEGF激活VEGFR1和VEGFR2的能力，并将检查VEGF调节VEGF活性的能力，包括：内皮细胞的迁移、巨噬细胞的趋化性和血管通透性。

Angiogenesis, the development of new vasculature from preexisting blood vessels, plays a critical role in many physiological processes and pathological events. An increased understanding of how angiogenesis is regulated in tissues would contribute to a variety of biological and medical areas. The extracellular matrix (ECM) and matricellular proteins found in the ECM function as important regulators of angiogenesis by their interaction with endothelial cells and the angiogenic factors that control blood vessel development. SPARC (secreted protein, acidic and rich in cysteine), a matricellular protein, has recently been shown to interact with and regulate the activity of vascular endothelial growth factor (VEGF), a primary stimulant of angiogenesis in both normal and pathological situations. An understanding of the proteins in the ECM that interact with VEGF and their ability to regulate VEGF activity would contribute to our understanding of VEGF-induced angiogenesis and its role in tissue homeostasis and pathology. In this application I will characterize further the interaction of SPARC and VEGF. The ability of SPARC to block VEGF from activating VEGFR1 an VEGFR2 will be determined and the ability of SPARC to regulate VEGF activities including: migration of endothelial cells, chemotaxis of macrophages, and vascular permeability will be examined.