In aged mice, functional maladaptation of cerebral arteries to hypertension is driven by dysregulation of pressure-induced 20-HETE and TRP channel-mediated smooth muscle cell calcium signaling.
In aged mice, impaired functional adaptation of cerebral arteries to hypertension is driven by dysregulation of 20-HETE and TRP channel-mediated calcium signaling rather than BK channel overactivation.
Hypertension in the elderly substantially increases the risk of stroke and vascular cognitive impairment in part due to an impaired functional adaptation of aged cerebral arteries to high blood pressure. To elucidate the mechanisms underlying impaired autoregulatory protection in aging, hypertension was induced in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic infusion of angiotensin II and pressure-induced changes in smooth muscle cell (SMC) intracellular Ca(2+) concentration (Ca(2+)i) and myogenic constriction of middle cerebral arteries (MCA) were assessed. In MCAs from young hypertensive mice, pressure-induced increases in vascular SMC Ca(2+)i and myogenic tone were increased, and these adaptive responses were inhibited by the cytochrome P-450 ω-hydroxylase inhibitor HET0016 and the transient receptor potential (TRP) channel blocker SKF96365. Administration of 20- hydroxyeicosatetraenoic acid (HETE) increased SMC Ca(2+)i and constricted MCAs, and these responses were inhibited by SKF96365. MCAs from aged hypertensive mice did not show adaptive increases in pressure-induced calcium signal and myogenic tone and responses to HET0016 and SKF96365 were blunted. Inhibition of large-conductance Ca(2+)-activated K(+) (BK) channels by iberiotoxin enhanced SMC Ca(2+)i and myogenic constriction in MCAs of young normotensive animals, whereas it was without effect in MCAs of young hypertensive mice. Iberiotoxin did not restore myogenic adaptation in MCAs of aged hypertensive mice. Thus functional maladaptation of aged cerebral arteries to hypertension is due to the dysregulation of pressure-induced 20-HETE and TRP channel-mediated SMC calcium signaling, whereas overactivation of BK channels is unlikely to play a role in this phenomenon.
Tóth et al. (Sat,) conducted a other in Hypertension and aging (n=80). Angiotensin II infusion vs. Saline vehicle was evaluated on Pressure-induced changes in smooth muscle cell intracellular Ca2+ concentration and myogenic constriction. In aged mice, functional maladaptation of cerebral arteries to hypertension is driven by dysregulation of pressure-induced 20-HETE and TRP channel-mediated smooth muscle cell calcium signaling.