Mechanisms and functions of CRACR2A-L Rab GTPase in vascular endothelial cells

血栓形成(血液凝结)是维持血管完整性和防止血管损伤后过度出血的重要过程。然而，异常的血栓形成会导致血管闭塞和动脉粥样硬化斑块的发展，从而导致高血压、中风或脑缺血。Von-Willebrand因子(VWF)介导的血小板黏附是血栓形成的主要调节因子，因此血管内皮细胞分泌vWF受到高度调控。血浆vWF水平升高被认为是心血管疾病的危险因素，特别是在糖尿病等高危人群中。VWF包含在特殊的储存囊中，称为韦贝尔帕拉德小体(WPBs)，在刺激下会迅速释放其成分。激动剂诱导的vWF分泌是一个钙依赖的过程，由称为Rab GTP酶的分子开关调节。将激动剂诱导的细胞内钙离子升高与Rab GTP酶激活结合起来的蛋白质仍然难以捉摸，尽管是几个研究小组的重点。然而，我们最近发现了一种在内皮细胞中表达的新的Rab GTP酶，与大多数Rab GTP酶家族不同的是，它含有钙结合结构域。本研究认为，钙离子结合的Rab GTP酶CRACR2a-L具有重要的功能，可能成为动脉粥样硬化性疾病新的治疗靶点。

Thrombus formation (blood clotting) is an essential process to maintain vascular integrity and prevent excessive bleeding after vessel damage. However abnormal thrombi formation leads to blood vessel occlusions and development of atherosclerotic plaques with subsequent hypertension, stroke or ischaemia. Von-Willebrand Factor (vWF)-mediated platelet adhesion is a major regulator of thrombus formation, therefore vWF secretion from endothelial cells is highly regulated. Increased plasma levels of vWF have been proposed as a risk factor for cardiovascular disease, especially in high risk groups such as diabetics. vWF is contained in special storage vesicles called Weibel Palade Bodies (WPBs) which rapidly release their constituents upon stimulation. Agonist induced vWF secretion is a Ca2+-dependent process and is regulated by molecular switches called Rab GTPases. The protein that couples the rise in agonist-induced intracellular Ca2+ to Rab GTPase activation has remained elusive despite being the focus of several research groups. However, we recently identified a novel Rab GTPase expressed in endothelial cells that, unlike the majority of the Rab GTPase family, contains Ca2+ binding domains. This research proposes that the Ca2+ binding Rab GTPase, CRACR2A-L, has important functions and could potentially be offered as a target for novel therapeutics for athero-thrombotic diseases.