不受控制的血管生成是各种病理状况的基础，例如癌症、年龄相关性黄斑变性（AMD）和增殖性糖尿病视网膜病变（PDR）。因此，靶向病理性血管生成已成为治疗癌症和新生血管眼病的有前景的策略。然而，目前针对 VEGF 信号传导的药物治疗取得的成功有限，这要么是因为抗 VEGF 疗法产生了耐药性，并产生了严重的副作用，包括癌症患者的肾毒性和心血管相关的不良反应，要么是患者玻璃体内注射后出现视网膜血管炎和眼内炎症。与 AMD 或 PDR。因此，迫切需要开发能够控制病理微环境的多个方面并调节异常血管生成过程的新策略。为此，有人提出血管正常化作为抗血管生成方法的替代方法；然而，这些策略仍然侧重于针对 VEGF 或 FGF 或 PDGF，这已显示出不良影响。除了这些生长因子之外，钙最近被认为是肿瘤血管生成的重要调节剂。本文概述了内皮细胞中主要钙通道、TRP 通道的作用，特别关注 TRPV4 及其下游信号通路在调节病理性血管生成和血管正常化中的作用。我们还重点介绍了肿瘤微环境通过 Rho/YAP/VEGFR2 机械转录途径调节 TRPV4 活性和内皮表型转化的最新发现。最后，我们提供了内皮 TRPV4 作为血管正常化和改进治疗的新型 VEGF 替代治疗靶点的观点。 © 2024 美国生理学会。 Compr Physiol 14:5389-5406, 2024。版权所有 © 2024 美国生理学会。版权所有。

Uncontrolled angiogenesis underlies various pathological conditions such as cancer, age-related macular degeneration (AMD), and proliferative diabetic retinopathy (PDR). Hence, targeting pathological angiogenesis has become a promising strategy for the treatment of cancer and neovascular ocular diseases. However, current pharmacological treatments that target VEGF signaling have met with limited success either due to acquiring resistance against anti-VEGF therapies with serious side effects including nephrotoxicity and cardiovascular-related adverse effects in cancer patients or retinal vasculitis and intraocular inflammation after intravitreal injection in patients with AMD or PDR. Therefore, there is an urgent need to develop novel strategies which can control multiple aspects of the pathological microenvironment and regulate the process of abnormal angiogenesis. To this end, vascular normalization has been proposed as an alternative for antiangiogenesis approach; however, these strategies still focus on targeting VEGF or FGF or PDGF which has shown adverse effects. In addition to these growth factors, calcium has been recently implicated as an important modulator of tumor angiogenesis. This article provides an overview on the role of major calcium channels in endothelium, TRP channels, with a special focus on TRPV4 and its downstream signaling pathways in the regulation of pathological angiogenesis and vascular normalization. We also highlight recent findings on the modulation of TRPV4 activity and endothelial phenotypic transformation by tumor microenvironment through Rho/YAP/VEGFR2 mechanotranscriptional pathways. Finally, we provide perspective on endothelial TRPV4 as a novel VEGF alternative therapeutic target for vascular normalization and improved therapy. © 2024 American Physiological Society. Compr Physiol 14:5389-5406, 2024.Copyright © 2024 American Physiological Society. All rights reserved.