Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
Int J Mol Sci. 2024 Sep 24;25(19):10254. doi: 10.3390/ijms251910254.
In the aging population, choroidal vessels grow through the Bruch's membrane, resulting in a loss of central vision due to choroidal neovascularization (CNV). During active neovascularization, CNV is associated with inappropriate levels of apoptosis in multiple cell types, including choroidal endothelial cells (ChECs). Bim is a pro-apoptotic member of the Bcl-2 family. It is essential for cell apoptosis due to exposure to drugs such as dexamethasone or decreased pro-survival factors, including vascular endothelial growth factor (VEGF). To better elucidate the cell autonomous contribution of Bim expression in the integrity and neovascularization of the choroidal vasculature, we isolated ChECs from wild-type and Bim-deficient (Bim) mice. ChECs lacking Bim expression demonstrated increased expression of VEGF, osteopontin, and the inflammatory cytokines Rantes/Ccl5 and IL6. Bim ChECs were more proliferative and demonstrated an increased capacity to undergo capillary morphogenesis. Anti-VEGF had a diminished capacity to disrupt capillary morphogenesis in Bim ChECs. In vivo, utilizing the mouse laser photocoagulation model, anti-VEGF treatment mitigated CNV in wild-type but not Bim mice. We also tested other modalities that are thought to not require the intrinsic death pathway for their function and showed that propranolol, anti-CTGF, and the TSP1-mimetic peptide ABT898 mitigated CNV in mice lacking Bim expression to varying degrees. Thus, in ChECs, Bim expression could impact the effectiveness of treatment modalities that require the intrinsic death pathway to mitigate CNV.
在老龄化人口中，脉络膜血管通过布鲁赫膜生长，导致脉络膜新生血管化（CNV）导致中心视力丧失。在活跃的新生血管化过程中，CNV与包括脉络膜内皮细胞（ChECs）在内的多种细胞类型的凋亡水平异常有关。Bim 是 Bcl-2 家族的促凋亡成员。由于接触地塞米松等药物或减少包括血管内皮生长因子（VEGF）在内的促生存因子，它对细胞凋亡至关重要。为了更好地阐明 Bim 表达在脉络膜血管完整性和新生血管化中的细胞自主贡献，我们从野生型和 Bim 缺陷型（Bim）小鼠中分离出 ChECs。缺乏 Bim 表达的 ChECs表现出更高水平的 VEGF、骨桥蛋白以及炎症细胞因子 Rantes/Ccl5 和 IL6 的表达。Bim ChECs 的增殖能力增强，并表现出更高的毛细血管形态发生能力。抗 VEGF 对 Bim ChECs 的毛细血管形态发生的破坏能力降低。在体内，利用小鼠激光光凝模型，抗 VEGF 治疗减轻了野生型但不是 Bim 小鼠的 CNV。我们还测试了其他被认为不需要内在死亡途径发挥作用的模式，并表明普萘洛尔、抗 CTGF 和 TSP1 模拟肽 ABT898 在不同程度上减轻了缺乏 Bim 表达的小鼠的 CNV。因此，在 ChECs 中，Bim 表达可能会影响需要内在死亡途径来减轻 CNV 的治疗模式的有效性。
