Endothelial retinoblastoma protein reduces abdominal aortic aneurysm development via promoting DHFR/NO pathway-mediated vasoprotection

Cardiovascular disease (CVD) is a major cause of global mortality. The proper functioning of the endothelial layer of arteries is crucial to cardiovascular health. Retinoblastoma protein (Rb), encoded by the Rb1 gene, has been shown to offer vasoprotective effects. Herein, we investigated endothelial Rb's effects on arterial function using an endothelial-specific conditional Rb1 knockout (Rb cKO) mouse model. We found that Rb deficiency reduced dihydrofolate reductase (DHFR) activity and downstream NO production in mouse aortic endothelial cells and blocked arterial vasodilation in an endothelial DHFR-dependent manner. Rb deficiency also increased phenylephrine-triggered arterial vasoconstriction, BP levels, and pathological aortic remodeling without significantly affecting prostanoid synthesis. Employing an angiotensin II (AngII)-stimulated apolipoprotein E knockout (apoE -/-) mice fed a standard, non-atherogenic diet, Rb deficiency increased aortic diameter, stimulated abdominal aortic aneurysm (AAA) development, and reduced survival. These pathological responses to Rb deficiency in AngII-stimulated apoE-/- mice were rescued by DHFR overexpression. Cumulatively, our findings reveal that endothelial Rb positively impacts arterial function by supporting vasoprotective endothelial DHFR/NO pathway activity, leading to reduced AAA development.

心血管疾病（CVD）是全球死亡的主要原因。动脉内皮细胞层的正常功能对心血管健康至关重要。由Rb1基因编码的视网膜母细胞瘤蛋白（Rb）已被证明具有血管保护作用。在此，我们利用一种内皮细胞特异性条件性Rb1基因敲除（Rb cKO）小鼠模型研究了内皮细胞Rb对动脉功能的影响。我们发现，Rb缺乏会降低小鼠主动脉内皮细胞中二氢叶酸还原酶（DHFR）的活性以及下游一氧化氮（NO）的产生，并以内皮细胞DHFR依赖的方式阻碍动脉血管舒张。Rb缺乏还会增加苯肾上腺素引发的动脉血管收缩、血压水平以及病理性主动脉重塑，而对前列腺素合成没有显著影响。采用血管紧张素II（AngII）刺激的载脂蛋白E基因敲除（apoE -/-）小鼠，并喂食标准的非致动脉粥样硬化饮食，Rb缺乏会增加主动脉直径，刺激腹主动脉瘤（AAA）的发展，并降低存活率。在AngII刺激的apoE -/-小鼠中，这些因Rb缺乏导致的病理反应可通过DHFR过表达得以挽救。总之，我们的研究结果表明，内皮细胞Rb通过支持具有血管保护作用的内皮细胞DHFR/NO通路活性，对动脉功能产生积极影响，从而减少腹主动脉瘤的发展。