Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension

Larry N. Agbor, Anand R. Nair, Jing Wu, Ko Ting Lu, Deborah R. Davis, Henry L. Keen, Frederick W. Quelle, James (Jim) McCormick, Jeffrey D. Singer, Curt D. Sigmund

Research output: Contribution to journalArticle

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 response to 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), a marked reduction in cGMP production, and impaired vasodilation to cGMP analogs. Vasodilation responses to a selective large-conductance Ca2+-activated K+ channel activator were normal, suggesting that downstream signals that 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 evidence that vascular smooth muscle CUL3 is a major regulator of BP. CUL3 mutations cause severe vascular dysfunction, arterial stiffness, and hypertension due to defects in vascular smooth muscle.

Original languageEnglish (US)
Article numbere129793.
JournalJCI Insight
Volume4
Issue number14
DOIs
StatePublished - Jul 25 2019

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Cullin Proteins
Smooth Muscle
Hypertension
Vascular Smooth Muscle
Vascular Stiffness
Vasodilation
Calcium-Activated Potassium Channels
Mutation
Smooth Muscle Myocytes
Blood Vessels
Aorta

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Agbor, L. N., Nair, A. R., Wu, J., Lu, K. T., Davis, D. R., Keen, H. L., ... Sigmund, C. D. (2019). Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension. JCI Insight, 4(14), [e129793.]. https://doi.org/10.1172/jci.insight.129793

Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension. / Agbor, Larry N.; Nair, Anand R.; Wu, Jing; Lu, Ko Ting; Davis, Deborah R.; Keen, Henry L.; Quelle, Frederick W.; McCormick, James (Jim); Singer, Jeffrey D.; Sigmund, Curt D.

In: JCI Insight, Vol. 4, No. 14, e129793., 25.07.2019.

Research output: Contribution to journalArticle

Agbor, LN, Nair, AR, Wu, J, Lu, KT, Davis, DR, Keen, HL, Quelle, FW, McCormick, JJ, Singer, JD & Sigmund, CD 2019, 'Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension', JCI Insight, vol. 4, no. 14, e129793.. https://doi.org/10.1172/jci.insight.129793
Agbor, Larry N. ; Nair, Anand R. ; Wu, Jing ; Lu, Ko Ting ; Davis, Deborah R. ; Keen, Henry L. ; Quelle, Frederick W. ; McCormick, James (Jim) ; Singer, Jeffrey D. ; Sigmund, Curt D. / Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension. In: JCI Insight. 2019 ; Vol. 4, No. 14.
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