Lin Ying-Yu, Warren Emily, Macklin Bria L, Ramirez Lucas, Gerecht Sharon
bioRxiv. 2025 Mar 10:2025.03.08.642174. doi: 10.1101/2025.03.08.642174.
Pericytes stabilize the microvasculature by enhancing endothelial barrier integrity, resulting in functional networks. During retinal development, pericyte recruitment is crucial for stabilizing nascent angiogenic vasculature. However, in adulthood, disrupted endothelial-pericyte interactions lead to vascular dropout and pathological angiogenesis in ocular microvascular diseases, and strategies to stabilize the retinal vasculature are lacking. We demonstrate that direct endothelial-pericyte contact downregulates pVEGFR2 in endothelial cells, which enhances pericyte migration and promotes endothelial cell barrier function. Intravitreal injection of a VEGFR2 inhibitor in mouse models of the developing retina and oxygen-induced retinopathy increased pericyte recruitment and aided vascular stability. The VEGFR2 inhibitor further rescued ischemic retinopathy by enhancing vascularization and tissue growth while reducing vascular permeability. Our findings offer a druggable target to support the growth of functional and mature microvasculature in ocular microvascular diseases and tissue regeneration overall.
周细胞通过增强内皮屏障完整性来稳定微血管系统，从而形成功能性网络。在视网膜发育过程中，周细胞募集对于稳定新生的血管生成血管系统至关重要。然而，在成年期，内皮细胞与周细胞之间的相互作用破坏会导致眼部微血管疾病中的血管缺失和病理性血管生成，并且缺乏稳定视网膜血管系统的策略。我们证明，内皮细胞与周细胞的直接接触会下调内皮细胞中的磷酸化血管内皮生长因子受体2（pVEGFR2），这会增强周细胞迁移并促进内皮细胞屏障功能。在发育中的视网膜和氧诱导性视网膜病变的小鼠模型中玻璃体内注射血管内皮生长因子受体2（VEGFR2）抑制剂可增加周细胞募集并有助于血管稳定。VEGFR2抑制剂通过增强血管生成和组织生长同时降低血管通透性，进一步挽救了缺血性视网膜病变。我们的研究结果提供了一个可药物作用的靶点，以支持眼部微血管疾病中功能性和成熟微血管系统的生长以及整体组织再生。
