Selective ablation of CUL3 (Cullin-3) in vascular smooth muscle cell-selective CUL3 knockout (S-CUL3KO) results in severe hypertension with paradoxically unaltered ANG II (angiotensin II) levels, suggesting an increase in ANG II sensitivity. Loss of CUL3 function enhances ANG II sensitivity by increasing TRPC6-mediated cytosolic calcium concentration flux in smooth muscle cells.