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.

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 hours/day, 5 days/week) 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 weeks but not for 4 or 8 weeks. These results were correlated with an increase in L-type Ca2+ channel activity in mesenteric arterial myocytes after 12 weeks of SHS exposure. Moreover, 12 weeks 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.

Vascular smooth muscle excitability is exquisitely regulated by different ion channels that control membrane potential (E m) and the magnitude of intracellular calcium inside the cell to induce muscle relaxation or contraction, which significantly influences the microcirculation. Among them, various members of the K + channel family, voltage-gated Ca 2+ channels, and transient receptor potential (TRP) channels are fundamental for control of vascular smooth muscle excitability. These ion channels exist in complex with numerous signaling molecules and binding partners that modulate their function and, in doing so, impact vascular smooth muscle excitability. In this book chapter, we will review our current understanding of some of these ion channels and binding partners in vascular smooth muscle and discuss how their regulation is critical for proper control of (micro)vascular function.

The L‐type channel CaV1.2 is essential for vascular smooth muscle contraction and arterial tone. Increased vascular CaV1.2 expression and function are related to high smooth muscle contractility and enhanced arterial tone during hypertension, which is characterized by enhanced angiotensin II (angII) signaling. Several pathways have been proposed to account for increased CaV1.2 expression during hypertension, including increased CaV1.2 trafficking. However, mechanisms underlying enhanced CaV1.2 function during angII signaling and hypertension remain a subject of intense investigation. In this study, we hypothesize that CaV1.2 phosphorylation at the S1928 site is a key event that mediates increased channel activity and vascular reactivity during angII signaling and hypertension. Initial experiments found increased S1928 phosphorylation in angII‐treated wild type arterial lysates. This was associated with elevated vascular smooth muscle whole‐cell L‐type channel currents, global intracellular Ca2+, and contraction. Similarly, ex vivo and in vivo experiments in mesenteric arteries reveal an increased arterial tone and decreased mesenteric blood flow from wild type mice. Moreover, smooth muscle cells treated with angII showed a redistribution of CaV1.2 into larger clusters. These functional changes were prevented or significantly ameliorated in arteries or cells from a knockin mouse expressing a mutant CaV1.2 in which serine was replaced with alanine at position 1928 (S1928A mouse) and by protein kinase C inhibition. In angII‐induced hypertensive mice, increased CaV1.2 clusters size and channel activity, enhanced arterial tone, and mean arterial pressure in wild type mice were prevented or significantly reduce in S1928A mice. Altogether, these results suggest a key role for phosphorylation of CaV1.2 at S1928 in regulating CaV1.2 distribution, activity, and vascular function during angII signaling and hypertension. Phosphorylation of this single vascular CaV1.2 amino acid could be an essential regulatory mechanism that could be exploited for therapeutic intervention.