Voltage-dependent Ca ²⁺ entry into smooth muscle during contraction promotes endothelium-mediated feedback vasodilation in arterioles

Abstract

Vascular smooth muscle contraction is suppressed by feedback dilation mediated by the endothelium. In skeletal muscle arterioles, this feedback can be activated by Ca signals passing from smooth muscle through gap junctions to endothelial cells, which protrude through holes in the internal elastic lamina to make contact with vascular smooth muscle cells. Although hypothetically either Ca or inositol trisphosphate (IP) may provide the intercellular signal, it is generally thought that IP diffusion is responsible. We provide evidence that Ca entry through L-type voltage-dependent Ca channels (VDCCs) in vascular smooth muscle can pass to the endothelium through positions aligned with holes in the internal elastic lamina in amounts sufficient to activate endothelial cell Ca signaling. In endothelial cells in which IP receptors (IPRs) were blocked, VDCC-driven Ca events were transient and localized to the endothelium that protrudes through the internal elastic lamina to contact vascular smooth muscle cells. In endothelial cells in which IPRs were not blocked, VDCC-driven Ca events in endothelial cells were amplified to form propagating waves. These waves activated voltage-insensitive, intermediate-conductance, Ca-activated K (IK) channels, thereby providing feedback that effectively suppressed vasoconstriction and enabled cycles of constriction and dilation called vasomotion. Thus, agonists that stimulate vascular smooth muscle depolarization provide Ca to endothelial cells to activate a feedback circuit that protects tissue blood flow.

Alpha1-adrenergic stimulation selectively enhances endothelium-mediated vasodilation in rat cremaster arteries

“…; Garland et al. ). As shown by the representative tracing in Figure A, myogenically active cremaster arteries exhibited typical dilatory responses to ACh, SKA‐31, and SNP, along with a robust and reversible constriction to bath‐applied 30 mmol/L KCl (N.B.…”

“…; Garland et al. ). In this study, we independently reproduce and expand these observations by describing a systematic characterization of VSM α 1 ‐adrenoceptor‐dependent modulation of endothelium‐mediated vasodilation in isolated, myogenically active resistance arteries from rat cremaster muscle.…”

“…; Garland et al. ). In particular, reports from Duling, Dora and coworkers have indicated that hormonal activation of vascular smooth muscle (VSM) α 1 ‐adrenoceptors in resistance arteries can lead to elevated intracellular Ca 2+ in the adjacent endothelial layer (Dora et al.…”

“…; Garland et al. ), which may subsequently impact endothelial function and regulation of vascular tone. In this study, we have hypothesized that concurrent α 1 ‐adrenoceptor activation will either positively or negatively influence endothelium‐dependent vasodilation, and this impact will depend upon the degree of α 1 ‐adrenoceptor activation (i.e., magnitude/direction of effect driven by the concentration of α 1 ‐adrenoceptor agonist).…”

VEGF‐A inhibits agonist‐mediated Ca2+ responses and activation of IKCa channels in mouse resistance artery endothelial cells

“…Ca 2+ data were analysed using subcellular regions of interest as described previously (Garland et al . 2017), with each event categorized when viewing the original movie file during manual frame‐by‐frame playback. If a response radiated from a single point and was also synchronized and rapidly decayed within 20 μm 2 , this was termed local; Ca 2+ waves were defined as asynchronous events that visibly propagated at least 20 μm along the length of an EC.…”