ArticleHypertension (Dallas, Tex. : 1979)2025
Role of the Renin-Angiotensin System in Blood Pressure Regulation in Smooth Muscle-Specific Cullin-3 Deficient Mice.
Article in Hypertension (Dallas, Tex. : 1979), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Vascular smooth muscle RbFox2 regulates the cytoskeleton and arterial stiffness by a RhoBTB1/Cullin-3 mechanism.JCI insight · 2026Article
- Cullin-3 regulates the renal baroreceptor machinery that controls renin gene expression.JCI insight · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
13 authors.
Funding
Abstract
backgroundSelective 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.
methodsBlood 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.
resultsS-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.
conclusionsCollectively, 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.
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