Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Vascular Research Lab, Providence Veterans Affairs Medical Center, Providence, Rhode Island, USA.
Compr Physiol. 2024 Mar 29;14(2):5389-5406. doi: 10.1002/cphy.c230014.
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.
不受控制的血管生成是多种病理状况的基础，如癌症、年龄相关性黄斑变性（AMD）和增生性糖尿病视网膜病变（PDR）。因此，针对病理性血管生成已成为治疗癌症和新生血管性眼病的一种有前途的策略。然而，目前针对 VEGF 信号的药理学治疗方法要么由于对针对 VEGF 的治疗产生耐药性而收效甚微，这些治疗方法具有严重的副作用，包括癌症患者的肾毒性和心血管相关副作用，要么由于 AMD 或 PDR 患者玻璃体内注射后出现视网膜血管炎和眼内炎症而收效甚微。因此，迫切需要开发新的策略，以控制病理性微环境的多个方面并调节异常血管生成的过程。为此，血管正常化已被提议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，这些药物已显示出不良反应。除了这些生长因子外，钙最近也被认为是肿瘤血管生成的重要调节剂。本文概述了主要钙通道在血管内皮中的作用、TRP 通道，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。我们还强调了肿瘤微环境通过 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，我们提供了内皮细胞 TRPV4 作为血管正常化和改善治疗的新型 VEGF 替代治疗靶点的观点。© 2024 美国生理学会。综合生理学 14:5389-5406, 2024。
