Arterial α2-Na+ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α2 mice

Abstract

Arterial myocytes express α1-catalytic subunit isoform Na+ pumps (75–80% of total), which are ouabain resistant in rodents, and high ouabain affinity α2-Na+ pumps. Mice with globally reduced α2-pumps (but not α1-pumps), mice with mutant ouabain-resistant α2-pumps, and mice with a smooth muscle (SM)-specific α2-transgene (α2SM-Tg) that induces overexpression all have altered blood pressure (BP) phenotypes. We generated α2SM-DN mice with SM-specific α2 (not α1) reduction (>50%) using nonfunctional dominant negative (DN) α2. We compared α2SM-DN and α2SM-Tg mice to controls to determine how arterial SM α2-pumps affect vasoconstriction and BP. α2SM-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 ANG II infusion (240 ng·kg−1·min−1) and high (6%) NaCl. Several arterial Ca2+ transporters, including Na+/Ca2+ exchanger 1 (NCX1) and sarcoplasmic reticulum and plasma membrane Ca2+ pumps [sarco(endo)plasmic reticulum Ca2+-ATPase 2 (SERCA2) and plasma membrane Ca2+-ATPase 1 (PMCA1)], were also reduced (>50%). α2SM-DN mouse isolated small arteries had reduced myogenic reactivity, perhaps because of reduced Ca2+ transporter expression. In contrast, α2SM-Tg mouse aortas overexpressed α2 (>2-fold), NCX1, SERCA2, and PMCA1 (43). α2SM-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−1·min−1) with or without 2% NaCl but normal myogenic reactivity. NCX1 expression was inversely related to basal BP in SM-α2 engineered mice but was directly related in SM-NCX1 engineered mice. NCX1, which usually mediates arterial Ca2+ entry, and α2-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-α2 engineered mice apparently compensates to minimize Ca2+ overload (α2SM-DN) or depletion (α2SM-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.