肾素-血管紧张素系统在平滑肌特异性Cullin-3基因缺陷小鼠血压调节中的作用
Role of the Renin-Angiotensin System in Blood Pressure Regulation in Smooth Muscle-Specific Cullin-3 Deficient Mice.
作者信息
Golosova Daria, Kumar Gaurav, Chaihongsa Nisita, Reho John J, Lu Ko-Ting, Brozoski Daniel T, Wackman Kelsey K, Lawton Samuel B R, Muskus Patricia C, Lin Brian L, Grobe Justin L, Nakagawa Pablo, Sigmund Curt D
机构信息
Department of Physiology, Medical College of Wisconsin, Milwaukee (D.G., G.K., N.C., J.J.R., K.-T.L., D.T.B., K.K.W., S.B.R.L., P.C.M., J.L.G., P.N., C.D.S.).
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee (B.L.L.).
出版信息
Hypertension. 2025 Jul;82(7):1208-1220. doi: 10.1161/HYPERTENSIONAHA.125.25045. Epub 2025 May 14.
BACKGROUND
Selective ablation of CUL3 (Cullin-3) in vascular smooth muscle cell-selective CUL3 knockout (S-CUL3KO) results in severe hypertension with paradoxically unaltered ANG II (angiotensin II) levels, suggesting an increase in ANG II sensitivity. We hypothesized that the hypertension and vascular dysfunction in S-CUL3KO mice are mediated by an exaggerated calcium response to ANG II in vascular smooth muscle cells.
METHODS
Blood pressure was measured by radiotelemetry in S-CUL3KO mice subjected to pharmacological inhibition of the renin-angiotensin system. Vascular function was evaluated in several arterial beds, and freshly isolated smooth muscle cells were used to elucidate the contribution of CUL3 to ANG II-induced cytosolic calcium concentration flux. The involvement of potential calcium channels was evaluated based on gene expression in carotid arteries and pharmacological studies.
RESULTS
S-CUL3KO mice exhibited severe hypertension with an enhanced depressor response following the administration of renin-angiotensin system inhibitors. Candesartan administration before induction of the CUL3 deletion revealed both nonrenin-angiotensin system and renin-angiotensin system components to the development of hypertension. Increased ANG II-induced vasoconstriction was observed in mesenteric and basilar arteries in S-CUL3KO mice. Freshly isolated smooth muscle cells from S-CUL3KO exhibited an excessive cytosolic calcium concentration flux in response to ANG II. Gene expression studies of carotid arteries from S-CUL3KO mice led us to hypothesize a potential role for TRPC6 (Transient Receptor Potential Cation Channel Subfamily C Member 6) in ANG II hyperresponsiveness. TRPC6 pharmacological inhibition blunted the exaggerated ANG II-induced cytosolic calcium concentration flux in smooth muscle cells, blunted ANG II-induced vasoconstriction and lowered blood pressure in S-CUL3KO mice.
CONCLUSIONS
Collectively, these data are consistent with the conclusion that loss of CUL3 function enhances ANG II sensitivity by increasing TRPC6-mediated cytosolic calcium concentration flux in smooth muscle cells.
背景
在血管平滑肌细胞中选择性敲除 Cul3（Cullin-3），即血管平滑肌细胞选择性 Cul3 基因敲除（S-CUL3KO），会导致严重高血压，而血管紧张素 II（ANG II）水平却反常地未改变，这表明 ANG II 敏感性增加。我们推测 S-CUL3KO 小鼠的高血压和血管功能障碍是由血管平滑肌细胞中对 ANG II 的钙反应过度介导的。
方法
通过无线电遥测技术测量接受肾素-血管紧张素系统药理抑制的 S-CUL3KO 小鼠的血压。在几个动脉床评估血管功能，并使用新鲜分离的平滑肌细胞来阐明 Cul3 对 ANG II 诱导的胞质钙浓度通量的作用。基于颈动脉中的基因表达和药理研究评估潜在钙通道的参与情况。
结果
S-CUL3KO 小鼠表现出严重高血压，在给予肾素-血管紧张素系统抑制剂后降压反应增强。在诱导 Cul3 缺失之前给予坎地沙坦揭示了高血压发展中肾素-血管紧张素系统和非肾素-血管紧张素系统成分。在 S-CUL3KO 小鼠的肠系膜动脉和基底动脉中观察到 ANG II 诱导的血管收缩增加。从 S-CUL3KO 新鲜分离的平滑肌细胞对 ANG II 表现出过度的胞质钙浓度通量。对 S-CUL3KO 小鼠颈动脉的基因表达研究使我们推测瞬时受体电位阳离子通道亚家族 C 成员 6（TRPC6）在 ANG II 高反应性中具有潜在作用。TRPC6 药理抑制减弱了平滑肌细胞中 ANG II 诱导的过度胞质钙浓度通量，减弱了 ANG II 诱导的血管收缩并降低了 S-CUL3KO 小鼠的血压。
结论
总体而言这些数据与以下结论一致，即 Cul3 功能丧失通过增加平滑肌细胞中 TRPC6介导的胞质钙浓度通量来增强 ANG II 敏感性。
Zotero 插件