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Arterial myocytes express α1 catalytic subunit isoform Na(+) pumps (75-80% of total), which are ouabain-resistant in rodents, and high ouabain affinity α2 pumps. Mice with globally-reduced α2 (but not α1) pumps, mice with mutant, ouabain-resistant α2, and mice with a smooth muscle (SM)-specific α2 transgene (α2(SM-Tg)) that induces overexpression, all have altered blood pressure (BP) phenotypes. We generated α2(SM-DN) mice with SM-specific α2 (not α1) reduction (>50%) using non-functional, dominant negative (DN) α2. We compared α2(SM-DN) and α2(SM-Tg) mice to controls to determine how arterial α2 pumps affect vasoconstriction and BP. α2(SM-DN) mice had elevated basal mean BP (telemetry MBP: 117±4 vs 106±1 mm Hg, P<0.01, n=7/7) and enhanced BP responses to chronic Ang II infusion (240 ng/kg/min) and high (6%) NaCl. Several arterial Ca(2+) transporters including Na/Ca exchanger-1 (NCX1), and sarcoplasmic reticulum (SR) and plasma membrane (PM) Ca(2+) pumps (SERCA2 and PMCA1), were also reduced by >50%. α2(SM-DN) mouse isolated small arteries had reduced myogenic reactivity (MR), perhaps because of reduced Ca(2+) transporter expression. In contrast, α2(SM-Tg) mouse aortas overexpress α2 (>2-fold), NCX1, SERCA2 and PMCA1 (42). α2(SM-Tg) mice had reduced basal MBP (104±1 vs 109±2 mm Hg, P<0.02, n=15/9) and attenuated BP responses to chronic Ang II (300-400 ng/kg/min) ± 2% NaCl, but normal MR. NCX1 expression is inversely related to basal BP in SM-α2 engineered mice, but directly related in SM-NCX1 engineered mice. α2 Na(+) pumps and NCX1, which usually mediates arterial Ca(2+) entry, co-localize at PM-SR junctions and are functionally coupled via the local Na(+) gradient to help regulate cell Ca(2+). Altered Ca(2+) transporter expression in SM-α2 engineered mice apparently compensates to minimize Ca(2+) overload (α2(SM-DN)) or depletion (α2(SM-Tg)) and attenuate BP changes. In contrast, Ca(2+) transporter up-regulation, observed in many rodent hypertension models, should enhance Ca(2+) entry and signaling, and contributes significantly to BP elevation.
PMID: 26209057 [PubMed - as supplied by publisher]