Role of the Renin-Angiotensin System in Blood Pressure Regulation in Smooth Muscle-Specific Cullin-3 Deficient Mice. Hypertension 2025 Jul;82(7):1208-1220
Date
05/29/2025Pubmed ID
40440505Pubmed Central ID
PMC12176512DOI
10.1161/HYPERTENSIONAHA.125.25045Scopus ID
2-s2.0-105005164668 (requires institutional sign-in at Scopus site) 1 CitationAbstract
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.
Author List
Golosova D, Kumar G, Chaihongsa N, Reho JJ, Lu KT, Brozoski DT, Wackman KK, Lawton SBR, Muskus PC, Lin BL, Grobe JL, Nakagawa P, Sigmund CDAuthors
Justin L. Grobe PhD Professor in the Physiology department at Medical College of WisconsinJohn J. Reho Research Scientist II in the Physiology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Angiotensin IIAnimals
Biphenyl Compounds
Blood Pressure
Calcium
Cullin Proteins
Disease Models, Animal
Hypertension
Male
Mice
Mice, Knockout
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Renin-Angiotensin System
TRPC Cation Channels
TRPC6 Cation Channel
Vasoconstriction
