Therapeutic targeting of angiophagy to achieve microvascular recanalization

摘要 血栓栓塞性微血管闭塞与许多急性缺血情况有关 包括中风和心肌梗死，这可能是“无复流”现象的部分原因。这个 纤溶系统和血流动力学冲洗被认为是清除闭塞的主要机制。 所有血管床中的血栓栓子，然而，我们已经表明，它们在 微血管水平。这在一定程度上可能是由于我们发现了一种机制，并将其称为“食血管”， 由此内皮板脂膜广泛包裹闭塞栓子，将它们困在血管内。 管腔，显著减少血液动力学洗涤，并限制对血浆纤溶酶的获取。在……里面 中风等情况下，血栓栓子的早期吞噬很可能是非常有害的，因为 它可防止大血管或闭塞血管自发性再通后远端微血管再通 在给予组织型纤溶酶原激活剂或机械取栓术后。我们假设 从药物上预防或延迟吞噬血管的早期阶段，可以改善 血栓栓子清除、微血管血流和生存能力，导致更好的缺血后结果。我们 目的发现调控血管内皮细胞可塑性各个阶段的信号通路。 过程，目的是确定潜在的治疗靶点。我们将使用创新的多学科 阐明这些机制的方法包括突变小鼠、药物操作和高 闭塞微血管的活体成像分辨率。此外，我们将测试我们的候选药物 短暂性脑缺血卒中的翻译模型。这些研究可能会增进我们对 微血管闭塞和再通的机制，并可以发现新的靶点，以防止一氧化氮。 中风和其他缺血情况下的复流现象。

SUMMARY Thromboembolic occlusions of the microvasculature are implicated in many acute ischemic conditions including stroke and myocardial infarction and may be partly responsible for the “no-reflow“ phenomenon. The fibrinolytic system and hemodynamic washout are considered the principal mechanisms for removing occlusive thromboemboli in all vascular beds, however we have shown that they have a high failure rate at the microvascular level. This may be partly due to a mechanism that we discovered and termed “angiophagy”, whereby endothelial lamellipodia extensively envelop occluding emboli, trapping them within the vascular lumen, markedly reducing hemodynamic washout and limiting access to plasma fibrinolytic enzymes. In conditions such as stroke, it is likely that the early stage of thromboembolus engulfment is highly detrimental as it prevents distal microvascular recanalization following spontaneous reopening of large occluded vessels or after tissue plasminogen activator administration or mechanical thrombectomy. We hypothesize that pharmacologically preventing or delaying the early engulfment stages of angiophagy, can improve thromboembolic washout, and microvascular flow and viability, leading to better post-ischemic outcomes. We aim to discover signaling pathways that regulate the various stages of endothelial plasticity involved in this process, with the goal of identifying potential therapeutic targets. We will use an innovative multidisciplinary approach to elucidate these mechanisms including mutant mice, pharmacological manipulations and high resolution intravital imaging of occluded microvessels. Additionally, we will test our candidate drugs in a translational model of transient ischemic stroke. These studies are likely to advance our understanding of mechanisms of microvascular occlusion and recanalization and could identify novel targets to prevent the no- reflow phenomenon in stroke and other ischemic conditions.