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Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension. JCI Insight 2019 06 11;5

Date

06/12/2019

Pubmed ID

31184598

Pubmed Central ID

PMC6675584

DOI

10.1172/jci.insight.129793

Scopus ID

2-s2.0-85070660042   11 Citations

Abstract

Patients with mutations in Cullin-3 (CUL3) exhibit severe early onset hypertension but the contribution of the smooth muscle remains unclear. Conditional genetic ablation of CUL3 in vascular smooth muscle (S-CUL3KO) causes progressive impairment in responsiveness to nitric oxide (NO), rapid development of severe hypertension, and increased arterial stiffness. Loss of CUL3 in primary aortic smooth muscle cells or aorta resulted in decreased expression of the NO receptor, soluble guanylate cyclase (sGC), causing a marked reduction in cGMP production and impaired vasodilation to cGMP analogues. Vasodilation responses to a selective large conductance Ca2+-activated K+-channel activator were normal suggesting that downstream signals which promote smooth muscle-dependent relaxation remained intact. We conclude that smooth muscle specific CUL3 ablation impairs both cGMP production and cGMP responses and that loss of CUL3 function selectively in smooth muscle is sufficient to cause severe hypertension by interfering with the NO-sGC-cGMP pathway. Our study provides compelling evidence for the sufficiency of vascular smooth muscle CUL3 as a major regulator of BP. CUL3 mutations cause severe vascular dysfunction, arterial stiffness and hypertension due to defects in vascular smooth muscle.

Author List

Agbor LN, Nair AR, Wu J, Lu KT, Davis DR, Keen HL, Quelle FW, McCormick JA, Singer JD, Sigmund CD

Author

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

Animals
Aorta
Cullin Proteins
Cyclic GMP
Disease Models, Animal
Genetic Predisposition to Disease
Hypertension
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth
Muscle, Smooth, Vascular
Mutation
Myocytes, Smooth Muscle
Nitric Oxide
Soluble Guanylyl Cyclase
Transcriptome
Vascular Stiffness
Vasodilation