Sympathetic nerve stimulation induces local endothelial Ca²⁺ signals to oppose vasoconstriction of mouse mesenteric arteries

Abstract

It is generally accepted that the endothelium regulates vascular tone independent of the activity of the sympathetic nervous system. Here, we tested the hypothesis that the activation of sympathetic nerves engages the endothelium to oppose vasoconstriction. Local inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) signals ("pulsars") in or near endothelial projections to vascular smooth muscle (VSM) were measured in an en face mouse mesenteric artery preparation. Electrical field stimulation of sympathetic nerves induced an increase in endothelial cell (EC) Ca(2+) pulsars, recruiting new pulsar sites without affecting activity at existing sites. This increase in Ca(2+) pulsars was blocked by bath application of the α-adrenergic receptor antagonist prazosin or by TTX but was unaffected by directly picospritzing the α-adrenergic receptor agonist phenylephrine onto the vascular endothelium, indicating that nerve-derived norepinephrine acted through α-adrenergic receptors on smooth muscle cells. Moreover, EC Ca(2+) signaling was not blocked by inhibitors of purinergic receptors, ryanodine receptors, or voltage-dependent Ca(2+) channels, suggesting a role for IP(3), rather than Ca(2+), in VSM-to-endothelium communication. Block of intermediate-conductance Ca(2+)-sensitive K(+) channels, which have been shown to colocalize with IP(3) receptors in endothelial projections to VSM, enhanced nerve-evoked constriction. Collectively, our results support the concept of a transcellular negative feedback module whereby sympathetic nerve stimulation elevates EC Ca(2+) signals to oppose vasoconstriction.

Update on vascular endothelial Ca2+signalling: A tale of ion channels, pumps and transporters

“…The endothelial Ca 2+ pulsars colocalize with the intermediate conductance, Ca 2+ -sensitive K + channels (KCa3.1) so that local Ca 2+ signals may be translated into a negative shift in VM which is rapidly transmitted to the adjacent VSMCs in terms of EDHF [399] . Consistently, sympathetic nerve stimulation activates α-adrenergic receptors on SMCs to recruit new pulsar sites in the adjoining ECs in order to oppose vasoconstriction [400] . The spatiotemporal summation of adjacent Ca 2+ puffs leads to a regenerative intracellular Ca 2+ wave that can spread throughout the cytosol at an average speed of 5-60 µm/s [118,393,401] .…”

Role of impaired endothelial cell Ca2+signaling in uteroplacental vascular dysfunction during diabetic rat pregnancy

“…Mechanical load in isolated EC sheets is minimal, providing a potential explanation for the low basal levels of EC [Ca 2ϩ ] i . On the other hand, two-way communications between ECs and SMCs in the walls of blood vessels are well documented (49,53). IP 3 generated in SMCs of pressurized arteries can diffuse to ECs through gap junctions of myoendothelial projections, resulting in Ca 2ϩ release from the endoplasmic reticulum (ER) and hyperpolarization of ECs due to the activation of intermediate-conductance Ca 2ϩ -actived K ϩ (IK Ca ) channels (43, 53).…”

“…These experiments were performed without preconstriction of the arteries with PE as recent studies (38,43,53) have indicated that Ca 2ϩ and/or inositol 1,4,5-trisphosphate (IP3) elevated in response to agonist stimulation of SMCs can diffuse to ECs through myoendothelial gap junctions and modulate endothelial Ca 2ϩ signaling. In separate experiments, AChinduced EC [Ca 2ϩ ]i responses were also studied using small EC sheets enzymatically isolated from uteroplacental arteries of control and diabetic rats.…”

Update on innovative initiatives for the American Journal of Physiology-Heart and Circulatory Physiology

“…We brought the complexities and importance of O-linked N-acetylglucosamine signaling into context by exploring the work of Facundo et al (25). In an engaging and entertaining podcast on the work by Nausch et al (67), we reached into the realm of calcium pulsars and communication between vascular smooth muscle and the endothelium. Integrating bench and bedside, we opened the door on work by Paulin et al (71) to discuss whether dehydroepiandrosterone, a commercially available natural steroid hormone and antioxidant, may be useful as a treatment for pulmonary hypertension.…”

“…We produced several podcasts in the field of vascular biology and microcirculation (7, 8, 10, 23,33,34,39,41,53,57,58,67,76,105,106,115,116), and we wish to highlight several key podcasts here. We discussed a human study that looked at the central blood pressure response to the cyclooxygenase inhibitor indomethacin in both old and young healthy adults (5), which addressed the question: What happens when you combine nonsteroidal anti-inflammatory drug-type pain medication and aging-induced arterial stiffening?…”