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Conditional knockout of smooth muscle‐specific Na/Ca exchanger type‐1 causes striking impairment of NO/cGMP‐mediated vasodilation
Author(s) -
Wang Youhua,
Chen Ling,
Li Meng,
Cha Helen,
Iwamoto Takahiro,
Zhang Jin
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1052.6
Subject(s) - vasodilation , endocrinology , phenylephrine , medicine , chemistry , mesenteric arteries , angiotensin ii , acetylcholine , vascular smooth muscle , blood pressure , artery , smooth muscle
The functions of smooth muscle (sm) Na/Ca exchanger (NCX) in the vasculature are controversial and poorly understood. To determine the possible roles of NCX in the vasculature, we developed a novel mouse model (SM‐NCX1 KO) in which the sm‐specific NCX type‐1 (NCX1) was conditionally knocked out using tamoxifen‐inducible Cre‐loxP recombination technique. SM‐NCX1 KO mice exhibit significantly lower blood pressure (BP) and attenuated Ang II‐salt‐induced hypertension (radio telemetry). Isolated, pressurized mesenteric small arteries from SM‐NCX1 KO mice, compared to control arteries, were characterized by: 1) ~90% reduced NCX1 protein expression; 2) attenuated myogenic reactivity; and 3) attenuated vasoconstrictor response to phenylephrine but not angiotensin II; 4) normal relaxation to nifedipine, iberiotoxin, and external Ca 2+ removal; but 5) significantly deteriorated endothelium‐dependent vasodilatory responses to acetylcholine, which could not be rescued by exogenous NO/cGMP donor, sodium nitroprosside or 8‐Br‐cGMP. The vasodilation in control arteries was also significantly blocked by lowering [Na + ] o and was enhanced in arteries from mice that overexpress sm‐specific NCX1. These findings suggest that 1) sm NCX1 activity is required ( viz. downstream modulator) for endothelium‐dependent NO/cGMP‐mediated vasodilation; 2) arterial NCX1 mediates net Ca 2+ influx that helps maintain basal vascular tone in small resistance arteries and BP under physiological conditions; 3) NCX1 contributes to the BP elevation in Ang II‐salt hypertension.