Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Genetics

Background:

• Cullin-3 (CUL3) mutations are linked to hypertension in pseudohypoaldosteronism type II (PHAII).
• The precise mechanisms, particularly extratubular roles, driving CUL3 mutation-induced hypertension remain unclear.

Purpose of the Study:

• To investigate the role of CUL3 mutations in vascular smooth muscle in causing hypertension.
• To elucidate the molecular mechanisms by which CUL3 mutations affect vascular function and blood pressure.

Main Methods:

• Selective expression of a CUL3 mutation (CUL3Δ9) in mouse smooth muscle.
• Assessment of RhoA activity, RhoA/Rho kinase signaling, vascular function, and blood pressure responses.
• In vitro studies using human aortic smooth muscle cells to examine CUL3 substrate turnover.

Main Results:

• Smooth muscle-specific CUL3Δ9 expression impaired endogenous CUL3 function, increasing RhoA activity and signaling.
• This resulted in vascular dysfunction, elevated baseline arterial pressure, and exacerbated hypertension with angiotensin II challenge.
• CUL3Δ9 expression reduced active CUL3 levels and impaired RhoA degradation in human aortic smooth muscle cells.

Conclusions:

• Selective CUL3Δ9 expression in vascular smooth muscle replicates human hypertension observed in CUL3Δ9 subjects.
• CUL3 mutations contribute to human hypertension via vascular smooth muscle dysfunction, specifically through impaired RhoA degradation by CUL3.