α1C S1928 Phosphorylation of CaV1.2 Channel Controls Vascular Reactivity and Blood Pressure.

BACKGROUND: Increased vascular CaV1.2 channel function causes enhanced arterial tone during hypertension. This is mediated by elevations in angiotensin II/protein kinase C signaling. Yet, the mechanisms underlying these changes are unclear. We hypothesize that α1C phosphorylation at serine 1928 (S1928) is a key event mediating increased CaV1.2 channel function and vascular reactivity during angiotensin II signaling and hypertension. METHODS AND RESULTS: The hypothesis was examined in freshly isolated mesenteric arteries and arterial myocytes from control and angiotensin II-infused mice. Specific techniques include superresolution imaging, proximity ligation assay, patch-clamp electrophysiology, Ca2+ imaging, pressure myography, laser speckle imaging, and blood pressure telemetry. Hierarchical "nested" and appropriate parametric or nonparametric t test and ANOVAs were used to assess statistical differences. We found that angiotensin II redistributed the CaV1.2 pore-forming α1C subunit into larger clusters. This was correlated with elevated CaV1.2 channel activity and cooperativity, global intracellular Ca2+ and contraction of arterial myocytes, enhanced myogenic tone, and altered blood flow in wild-type mice. These angiotensin II-induced changes were prevented/ameliorated in cells/arteries from S1928 mutated to alanine knockin mice, which contain a negative modulation of the α1C S1928 phosphorylation site. In angiotensin II-induced hypertension, increased α1C clustering, CaV1.2 activity and cooperativity, myogenic tone, and blood pressure in wild-type cells/tissue/mice were averted/reduced in S1928 mutated to alanine samples. CONCLUSIONS: Results suggest an essential role for α1C S1928 phosphorylation in regulating channel distribution, activity and gating modality, and vascular function during angiotensin II signaling and hypertension. Phosphorylation of this single vascular α1C amino acid could be a risk factor for hypertension that may be targeted for therapeutic intervention.

Secondhand Smoke Exposure Impairs Ion Channel Function and Contractility of Mesenteric Arteries.

Cigarette smoke, including secondhand smoke (SHS), has significant detrimental vascular effects, but its effects on myogenic tone of small resistance arteries and the underlying mechanisms are understudied. Although it is apparent that SHS contributes to endothelial dysfunction, much less is known about how this toxicant alters arterial myocyte contraction, leading to alterations in myogenic tone. The study's goal is to determine the effects of SHS on mesenteric arterial myocyte contractility and excitability. C57BL/6J male mice were randomly assigned to either filtered air (FA) or SHS (6 h/d, 5 d/wk) exposed groups for a 4, 8, or 12-weeks period. Third and fourth-order mesenteric arteries and arterial myocytes were acutely isolated and evaluated with pressure myography and patch clamp electrophysiology, respectively. Myogenic tone was found to be elevated in mesenteric arteries from mice exposed to SHS for 12 wk but not for 4 or 8 wk. These results were correlated with an increase in L-type Ca2+ channel activity in mesenteric arterial myocytes after 12 wk of SHS exposure. Moreover, 12 wk SHS exposed arterial myocytes have reduced total potassium channel current density, which correlates with a depolarized membrane potential (Vm). These results suggest that SHS exposure induces alterations in key ionic conductances that modulate arterial myocyte contractility and myogenic tone. Thus, chronic exposure to an environmentally relevant concentration of SHS impairs mesenteric arterial myocyte electrophysiology and myogenic tone, which may contribute to increased blood pressure and risks of developing vascular complications due to passive exposure to cigarette smoke.

Cellular and molecular effects of hyperglycemia on ion channels in vascular smooth muscle.

Diabetes affects millions of people worldwide. This devastating disease dramatically increases the risk of developing cardiovascular disorders. A hallmark metabolic abnormality in diabetes is hyperglycemia, which contributes to the pathogenesis of cardiovascular complications. These cardiovascular complications are, at least in part, related to hyperglycemia-induced molecular and cellular changes in the cells making up blood vessels. Whereas the mechanisms mediating endothelial dysfunction during hyperglycemia have been extensively examined, much less is known about how hyperglycemia impacts vascular smooth muscle function. Vascular smooth muscle function is exquisitely regulated by many ion channels, including several members of the potassium (K+) channel superfamily and voltage-gated L-type Ca2+ channels. Modulation of vascular smooth muscle ion channels function by hyperglycemia is emerging as a key contributor to vascular dysfunction in diabetes. In this review, we summarize the current understanding of how diabetic hyperglycemia modulates the activity of these ion channels in vascular smooth muscle. We examine underlying mechanisms, general properties, and physiological relevance in the context of myogenic tone and vascular reactivity.