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

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.

SUBMITTER: Agbor LN

PROVIDER: S-EPMC6675584 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Agbor Larry N LN Nair Anand R AR Wu Jing J Lu Ko-Ting KT Davis Deborah R DR Keen Henry L HL Quelle Frederick W FW McCormick James A JA Singer Jeffrey D JD Sigmund Curt D CD

JCI insight 20190611

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 ...[more]

PMID: 31184598

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Project description:ObjectiveMutations in BMPR2 (bone morphogenetic protein receptor 2) are associated with familial and sporadic pulmonary arterial hypertension (PAH). The functional and molecular link between loss of BMPR2 in pulmonary artery smooth muscle cells (PASMC) and PAH pathogenesis warrants further investigation, as most investigations focus on BMPR2 in pulmonary artery endothelial cells. Our goal was to determine whether and how decreased BMPR2 is related to the abnormal phenotype of PASMC in PAH.MethodsSMC-specific Bmpr2-/- mice (BKOSMC) were created and compared to controls in room air, after 3 weeks of hypoxia as a second hit, and following 4 weeks of normoxic recovery. Echocardiography, right ventricular systolic pressure, and right ventricular hypertrophy were assessed as indices of pulmonary hypertension. Proliferation, contractility, gene and protein expression of PASMC from BKOSMC mice, human PASMC with BMPR2 reduced by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation were compared to controls, to investigate the phenotype and underlying mechanism.ResultsBKOSMC mice showed reduced hypoxia-induced vasoconstriction and persistent pulmonary hypertension following recovery from hypoxia, associated with sustained muscularization of distal pulmonary arteries. PASMC from mutant compared to control mice displayed reduced contractility at baseline and in response to angiotensin II, increased proliferation and apoptosis resistance. Human PASMC with reduced BMPR2 by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation showed a similar phenotype related to upregulation of pERK1/2 (phosphorylated extracellular signal related kinase 1/2)-pP38-pSMAD2/3 mediating elevation in ARRB2 (β-arrestin2), pAKT (phosphorylated protein kinase B) inactivation of GSK3-beta, CTNNB1 (β-catenin) nuclear translocation and reduction in RHOA (Ras homolog family member A) and RAC1 (Ras-related C3 botulinum toxin substrate 1). Decreasing ARRB2 in PASMC with reduced BMPR2 restored normal signaling, reversed impaired contractility and attenuated heightened proliferation and in mice with inducible loss of BMPR2 in SMC, decreasing ARRB2 prevented persistent pulmonary hypertension.ConclusionsAgents that neutralize the elevated ARRB2 resulting from loss of BMPR2 in PASMC could prevent or reverse the aberrant hypocontractile and hyperproliferative phenotype of these cells in PAH.

Dataset Information

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

Publications

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

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