Supplement - Regulation of Blood Pressure Circadian Rhythm by Vascular Smooth Muscle BMAL1

Blood pressure (BP) exhibits circadian rhythm and its disruption is often seen in hypertensive and diabetic patients and is associated with worsened cardiovascular outcomes. Premenopausal women have a lower BP than men but postmenopausal women have a higher BP and a significant higher progression rate of BP circadian rhythm disruption than men and premenopausal women, suggesting that sex hormone estrogen has a profound effect on BP circadian rhythm. With the overwhelming body of evidences for a critical role of estrogen in production of cardiovascular diseases, there are some evidences indicating that estrogen may be also involved in BP circadian rhythm regulation. In particular, estrogen has a diurnal rhythm over the 24-h period during menstrual cycle. Estrogen receptor beta (ERâ) that is more important in BP and vascular tone modulation exhibits a circadian expression in a BMAL1 dependent manner. Importantly, treatment of postmenopausal hypertensive patients with physiological doses of estrogen not only reduced BP levels but restored the normal amplitude of the circadian BP rhythm. Consistent with these findings, our preliminary data show that BP circadian rhythm and vascular smooth muscle contractile circadian variation (VSMCCV) are significantly disrupted in smooth muscle specific BMAL1 knockout mice (SM-bmal1-/-), and our recent publications demonstrated that BMAL1 circadian expression and BP circadian rhythm are severely disrupted in type 2 diabetic db/db mice. Based these information, we hypothesize that smooth muscle specific BMAL1 regulates the effect of gender difference on type 2 diabetes-associated disruption of BP circadian rhythm and VSMCCV. Two specific aims are: 1) Determine the effect of gender difference on diabetesassociated disruption of BP circadian rhythm and VSMCCV; 2) Determine the effect of gender difference on smooth muscle specific BMAL1-mediated disruptions of BP circadian rhythm and VSMCCV in type 2 diabetes. To achieve these goals, db/db mice that mimic human type diabetes and a novel SM-bmal1-/- mouse model will be used. BP circadian rhythm will be recorded by radiotelemetry. VSMCCV will be measured in isolated mesenteric arteries. Results will be compared and analyzed between male and female mice.