Arterial alpha_2-Na+ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific a2 mice

摘要

Arterial myocytes express ai-cat-alytic subunit isoform Na+ pumps (75-80% of total), which are ouabain resistant in rodents, and high ouabain affinity a2-Na+ pumps. Mice with globally reduced a2-pumps (but not ai-pumps), mice with mutant ouabain-resistant a2-pumps, and mice with a smooth muscle (SM)-specific a2-transgene (a2SM Tg) that induces overexpression all have altered blood pressure (BP) phenotypes. We generated a2SMDN mice with SM-specific a2 (not aO reduction (>50%) using nonfunctional dominant negative (DN) a2. We compared a2SM~DN and a2SM-Tg j^^ t0 consols to determine how arterial SM a2-pumps affect vasoconstriction and BP. et2SM~DN mice had elevated basal mean BP (mean BP by telemetry: 117 ± 4 vs. 106 ± 1 mmHg, n = 7/7, P < 0.01) and enhanced BP responses to chronic ANGII infusion (240 ng-kg-^min"1) and high (6%) NaCl. Several arterial Ca2+ transporters, including Na+/Ca2+ exchanger 1 (NCX1) and sarcoplas-mic reticulum and plasma membrane Ca2+ pumps [sarco(endo)plas-mic reticulum Ca2+-ATPase 2 (SERCA2) and plasma membrane Ca2+-ATPase 1 (PMCA1)], were also reduced (>50%). a2SMDN mouse isolated small arteries had reduced myogenic reactivity, perhaps because of reduced Ca2+ transporter expression. In contrast, a2sM-Tg mouse aortas overexpressed a2 (>2-fold), NCX1, SERCA2, and PMCA1 (43). a2SM"Tg mice had reduced basal mean BP (104 ± 1 vs. 109 ± 2 mmHg, n = 15/9, P < 0.02) and attenuated BP responses to chronic ANG II (300-400 ng-kg-^min"1) with or without 2% NaCl but normal myogenic reactivity. NCX1 expression was inversely related to basal BP in SM-a2 engineered mice but was directly related in SM-NCX1 engineered mice. NCX1, which usually mediates arterial Ca2+ entry, and a2-Na+ pumps colocalize at plasma membrane-sarcoplasmic reticulum junctions and functionally couple via the local Na+ gradient to help regulate cell Ca2+. Altered Ca2+ transporter expression in SM-a2 engineered mice apparently compensates to minimize Ca2+ overload (a2SM"DN) or depletion (a2SM~Tg) and attenuate BP changes. In contrast, Ca2+ transporter upregulation, observed in many rodent hypertension models, should enhance Ca2+ entry and signaling and contribute significantly to BP elevation.