Defining a novel molecular mechanism in VEGF-induced vascular hyperpermeability

血管疾病可能导致失明、肺功能障碍、中风和心脏病发作，这要么是因为血液流动不畅使组织缺乏氧气和营养，要么是因为缺氧组织中的血管经常渗漏，从而导致组织肿胀并促进炎症。用生长因子VEGF治疗性刺激新血管生长是治疗这些病症的有希望的治疗方法。然而，在成人中用VEGF刺激血管生长的副作用是血管渗漏增加，这会损害器官功能，特别是如果它发生在心脏、大脑、眼睛和肺中。为了了解VEGF引起血管生长或血管渗漏的机制，我们改变了其通过称为NRP1的分子发出信号的能力，NRP1将VEGF的信号传递到形成血管内层的内皮细胞中。我们的初步实验表明，NRP1可以以特定的方式靶向阻断血管渗漏，而不影响血管生长。为了确定NRP1引起血管渗漏的机制，我们将在影响眼睛，皮肤或肺血管功能的实验模型中改变其功能，并使用内皮细胞的组织培养模型来定义NRP1与其他信号分子的相互作用，这些信号分子在血管渗漏中发挥关键作用。我们的研究结果将提供关于血管渗漏如何在具有功能障碍的血管的急性和慢性疾病中被阻止的关键信息。这项研究不会立即产生临床影响，但可能有助于其他研究人员设计更好的治疗方法，可以阻止血管泄漏，并在不增加组织肿胀的情况下刺激新血管生长。

Blood vessel disease can cause blindness, lung dysfunction, stroke and heart attacks, either because poor blood flow starves tissues of oxygen and nutrients or because blood vessels in oxygen-starved tissues are often leaky and thereby cause tissue swelling and promote inflammation. The therapeutic stimulation of new vessel growth with the growth factor VEGF is a promising treatment for these conditions. However, a side effect of stimulating blood vessel growth with VEGF in adults is increased blood vessel leak that impairs organ function, especially if it occurs in the heart, brain, eye and lung. To understand the mechanism through which VEGF causes either blood vessel growth or blood vessel leak, we have altered its ability to signal through a molecule termed NRP1, which conveys signals from VEGF into the endothelial cells that form the inner lining of blood vessels. Our pilot experiments suggest that NRP1 can be targeted in a specific way to block blood vessel leak without affecting blood vessel growth. To identify the mechanism through which NRP1 causes blood vessel leak, we will alter its function in experimental models that affect eye, skin or lung vessel function and use tissue culture models of endothelial cells to define NRP1's interactions with other signalling molecules that play key roles in vascular leak. Our findings will provide key information on how vessel leak might be stemmed in acute and chronic diseases with dysfunctional blood vessels. This research will not have an immediate clinical impact, but may help other researchers to design better therapies that can stem vessel leak and allow the stimulation of new vessel growth without increasing tissue swelling.