Bywaters Briana C, Pedraza Gladys, Trache Andreea, Rivera Gonzalo M
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, United States.
Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX, United States.
Front Cardiovasc Med. 2022 Aug 12;9:955027. doi: 10.3389/fcvm.2022.955027. eCollection 2022.
A better understanding of endothelial dysfunction holds promise for more effective interventions for atherosclerosis prevention and treatment. Endothelial signaling by the non-catalytic region of the tyrosine kinase (NCK) family of adaptors, consisting of NCK1 and NCK2, has been implicated in cardiovascular development and postnatal angiogenesis but its role in vascular disease remains incompletely understood. Here, we report stage- and sex-dependent effects of endothelial NCK2 signaling on arterial wall inflammation and atherosclerosis development. Male and female -null atheroprone mice enabling inducible, endothelial-specific inactivation were fed a high fat diet (HFD) for 8 or 16 weeks to model atherosclerosis initiation and progression, respectively. Analysis of aorta preparations during disease progression, but not initiation, showed a significant reduction in plaque burden in males, but not females, lacking endothelial NCK2 relative to controls. Markers of vascular inflammation were reduced by endothelial NCK2 deficiency in both males and females during atherosclerosis progression but not initiation. At advanced stages of disease, plaque size and severity of atherosclerotic lesions were reduced by abrogation of endothelial NCK2 signaling only in males. Collectively, our results demonstrate stage- and sex-dependent modulation of atherosclerosis development by endothelial NCK2 signaling.
更好地理解内皮功能障碍有望为动脉粥样硬化的预防和治疗提供更有效的干预措施。由衔接蛋白酪氨酸激酶（NCK）家族的非催化区域（由NCK1和NCK2组成）介导的内皮信号传导已被证明与心血管发育和出生后血管生成有关，但其在血管疾病中的作用仍未完全明确。在此，我们报告了内皮NCK2信号传导对动脉壁炎症和动脉粥样硬化发展的阶段和性别依赖性影响。我们分别给可诱导、内皮特异性失活的雄性和雌性易患动脉粥样硬化小鼠喂食高脂饮食（HFD）8周或16周，以模拟动脉粥样硬化的起始和进展过程。在疾病进展（而非起始）阶段对主动脉标本进行分析，结果显示，相对于对照组，缺乏内皮NCK2的雄性小鼠斑块负担显著减轻，而雌性小鼠则不然。在动脉粥样硬化进展（而非起始）阶段，内皮NCK2缺乏可降低雄性和雌性小鼠的血管炎症标志物水平。在疾病晚期，仅在雄性小鼠中，通过消除内皮NCK2信号传导可减小斑块大小并减轻动脉粥样硬化病变的严重程度。总体而言，我们的结果表明内皮NCK2信号传导对动脉粥样硬化发展具有阶段和性别依赖性调节作用。
