Conditional knockout of smooth muscle sodium calcium exchanger type-1 lowers blood pressure and attenuates Angiotensin II-salt hypertension

Abstract

The functions of smooth muscle sodium calcium exchanger (NCX) in the vasculature are controversial and poorly understood. To determine the possible roles of NCX in the vascular phenotype and function, we developed a novel mouse model (SM‐NCX1 KO) in which the smooth muscle‐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 and attenuated angiotensin II (Ang II)‐salt‐induced hypertension (measured by radio telemetry and intra‐arterial catheterization). Isolated, pressurized mesenteric small resistance arteries from SM‐NCX1 KO mice, compared to control arteries, were characterized by the following: (1) ~90% reduced NCX1 protein expression; (2) impaired functional responses to (i) acute NCX inhibition by SEA0400 or SN‐6, (ii) NCX activation by low [Na+]o, and (iii) Na+ pump inhibition by ouabain; (3) attenuated myogenic reactivity; and (4) attenuated vasoconstrictor response to phenylephrine but not Ang II. These results provided direct evidence that arterial NCX1 normally mediates net Ca2+ influx that helps maintain basal vascular tone in small resistance arteries and blood pressure under physiological conditions. Importantly, NCX1 contributes to blood pressure elevation in Ang II‐salt hypertension, possibly by regulating α‐adrenergic receptor activation.

Arterial α2-Na+pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α2mice

“…In earlier studies, we observed that MT and MR were correlated directly with basal BP in ␣ 2 ϩ/Ϫ mice (57) and in mice with SM-specific KO (53,58) and SM-specific overexpression (18) of NCX1 (NCX1 SM-KO and NCX1 SM-Tg , respectively). This, plus the aforementioned reasoning about Ca 2ϩ homeostasis and the reported association between arterial tone in vivo and in isolated arteries (8), led us to anticipate that MR might be inversely correlated with arterial ␣ 2 -Na ϩ pump ex- pression.…”

“…In the latter, basal BP correlated directly with arterial NCX1 expression (18,53,58) (Figs. 3 and 4), whereas basal BP is reduced in ␣ 2 SM-Tg mice even though NCX1 is overexpressed (Fig.…”

“…Also, membrane potential plays an important role in the generation of MT (23), and transporters that affect membrane potential might also be altered in engineered mice. Some of these factors, for example, the greatly reduced expression of NCX1, which mainly mediates Ca 2ϩ entry in ASMCs (18,53,58), and SERCA2 (Fig. 3), may contribute to the delayed generation of MT (22,46) in ␣ 2 SM-DN mouse arteries.…”

“…This view is bolstered by reports that basal BP is inversely correlated with ASMC NCX1 expression in mice with SM-specific genetic modification of NCX1 expression (18,53,58). We discuss how this helps explain the finding that the BP phenotypes in SM-␣ 2 engineered mice are only modestly different from those of wildtype (WT) control mice even though ␣ 2 -Na ϩ pump activity apparently has a major influence on Ca 2ϩ homeostasis and contractile regulation.…”

Pivotal role of α2 Na+ pumps and their high affinity ouabain binding site in cardiovascular health and disease

“… b ; Wang et al . ). We infer that the EO‐induced, α2‐mediated increase in arterial NCX1 and SERCA2 expression, observed in many types of hypertension (Blaustein & Hamlyn, ; Blaustein et al .…”