Conditional Deletion of Smooth Muscle Cullin-3 Causes Severe Progressive Hypertension
his work was supported through research grants from the NIH to CDS (HL084207, HL125603, HL131689, HL144807) and JAM (DK098141) and from the American Heart Association (AHA; 15SFRN23480000) to CDS. This work was supported in part by an Iowa Cardiovascular Interdisciplinary Research Fellowship (T32HL007121) to LNA and an AHA postdoctoral fellowship to JW (17POST33660685).
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.
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Agbor, L. N., Nair, A. R., Wu, J., Lu, K.-T., Davis, D. R., Keen, H. L., Quelle, F. W., McCormick, J. A., Singer, J. D., & Sigmund, C. D. (2019). Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension. JCI Insight, 4(14). https://doi.org/10.1172/JCI.INSIGHT.129793