A close association between pericytes and endothelial cells (ECs) is crucial to the stability and function of capillary blood vessels and microvessels. The loss or dysfunction of pericytes results in significant disruption of these blood vessels as observed in pathological conditions, including cancer, diabetes, stroke, and Alzheimer’s disease. Prostaglandin E2 (PGE2) is a lipid mediator of inflammation, and its tissue concentration is elevated in cancer and neurological disorders. Here, we show that the exposure to PGE2 switches pericytes to a fast-migrating, loosely adhered phenotype that fails to intimately interact with ECs. N-cadherin and connexin-43 in adherens junction and gap junction between pericytes and ECs are downregulated by EP-4 and EP-1-dependent mechanisms, leading to breakdown of the pericyte–EC interaction. Furthermore, R-Ras, a small GTPase important for vascular normalization and vessel stability, is transcriptionally repressed by PGE2 in an EP4-dependent manner. Mouse dermal capillary vessels lose pericyte coverage substantially upon PGE2 injection into the skin. Our results suggest that EP-mediated direct disruption of pericytes by PGE2 is a key process for vascular destabilization. Restoring pericyte–EC interaction using inhibitors of PGE2 signaling may offer a therapeutic strategy in cancer and neurological disorders, in which pericyte dysfunction contributes to the disease progression.

周细胞和内皮细胞 (EC) 之间的密切关联对毛细血管和微血管的稳定性和功能至关重要。周细胞的丧失或功能障碍导致这些血管的严重破坏，如在病理状况中所观察到的，包括癌症、糖尿病、中风和阿尔茨海默病。前列腺素 E2 (PGE2) 是炎症的脂质介质，其组织浓度在癌症和神经系统疾病中升高。在这里，我们表明暴露于 PGE2 将周细胞切换为快速迁移、松散粘附的表型，该表型无法与 EC 密切相互作用。N-cadherin 和 connexin-43 在周细胞和 ECs 之间的粘附连接和间隙连接中被 EP-4 和 EP-1 依赖性机制下调，导致周细胞-EC 相互作用的破坏。此外，R-Ras，一种对血管正常化和血管稳定性很重要的小 GTP 酶，以 EP4 依赖性方式被 PGE2 转录抑制。将 PGE2 注射到皮肤中后，小鼠真皮毛细血管会显着失去周细胞覆盖。我们的结果表明，EP 介导的 PGE2 对周细胞的直接破坏是血管不稳定的关键过程。使用 PGE2 信号传导抑制剂恢复周细胞-EC 相互作用可能为癌症和神经系统疾病提供治疗策略，其中周细胞功能障碍有助于疾病进展。我们的结果表明，EP 介导的 PGE2 对周细胞的直接破坏是血管不稳定的关键过程。使用 PGE2 信号传导抑制剂恢复周细胞-EC 相互作用可能为癌症和神经系统疾病提供治疗策略，其中周细胞功能障碍有助于疾病进展。我们的结果表明，EP 介导的 PGE2 对周细胞的直接破坏是血管不稳定的关键过程。使用 PGE2 信号传导抑制剂恢复周细胞-EC 相互作用可能为癌症和神经系统疾病提供治疗策略，其中周细胞功能障碍有助于疾病进展。