Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice.
Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice.
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DOI：
10.1152/ajpheart.00377.2013
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发表时间：
2013-12
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影响因子：
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通讯作者：
Peter Toth;A. Csiszar;Zsuzsanna Tucsek;D. Sosnowska;Tripti Gautam;A. Koller;M. Schwartzman;W. Sonntag-W.
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文献类型：
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作者：
Peter Toth;A. Csiszar;Zsuzsanna Tucsek;D. Sosnowska;Tripti Gautam;A. Koller;M. Schwartzman;W. Sonntag-W.
老年人高血压大大增加了中风和血管性认知障碍的风险，部分原因是老年人脑动脉对高血压的功能适应受损。为了阐明衰老过程中自身调节保护功能受损的机制，我们通过慢性血管紧张素II输注年轻（3个月）和老年（24个月）C57BL/6小鼠诱导高血压，并评估了压力诱导的平滑肌细胞（SMC）细胞内Ca（2+）浓度（[Ca(2+)]i）的变化和大脑中动脉（MCA）的肌源性收缩。在年轻高血压小鼠的MCAs中，压力诱导的血管SMC [Ca(2+)]i和肌原性张力升高，这些适应性反应被细胞色素P-450 ω-羟化酶抑制剂HET0016和瞬时受体电位（TRP）通道阻滞剂SKF96365抑制。20-羟基二碳四烯酸（HETE）增加了SMC [Ca(2+)]i，收缩了MCAs， SKF96365抑制了这些反应。老年高血压小鼠的MCAs没有表现出压力诱导的钙信号和肌张力的适应性增加，HET0016和SKF96365的反应被减弱。iberiotoxin抑制大电导Ca（2+）激活的K(+) （BK）通道可增强年轻正常血压动物MCAs中的SMC [Ca(2+)]i和肌原性收缩，而对年轻高血压小鼠MCAs无影响。伊比利亚毒素不能恢复老年高血压小鼠mca的肌原性适应。因此，老年脑动脉对高血压的功能失调是由于压力诱导的20-HETE和TRP通道介导的SMC钙信号失调，而BK通道的过度激活不太可能在这一现象中起作用。
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.