CGRP signalling inhibits NO production through pannexin-1 channel activation in endothelial cells

Abstract

Blood flow distribution relies on precise coordinated control of vasomotor tone of resistance arteries by complex signalling interactions between perivascular nerves and endothelial cells. Sympathetic nerves are vasoconstrictors, whereas endothelium-dependent NO production provides a vasodilator component. In addition, resistance vessels are also innervated by sensory nerves, which are activated during inflammation and cause vasodilation by the release of calcitonin gene-related peptide (CGRP). Inflammation leads to superoxide anion (O 2 • − ) formation and endothelial dysfunction, but the involvement of CGRP in this process has not been evaluated. Here we show a novel mechanistic relation between perivascular sensory nerve-derived CGRP and the development of endothelial dysfunction. CGRP receptor stimulation leads to pannexin-1-formed channel opening and the subsequent O 2 • − -dependent connexin-based hemichannel activation in endothelial cells. The prolonged opening of these channels results in a progressive inhibition of NO production. These findings provide new therapeutic targets for the treatment of the inflammation-initiated endothelial dysfunction.

Sensory neurons from dorsal root ganglia regulate endothelial cell function in extracellular matrix remodelling

“…Calcitonin gene-related peptide (CGRP) and substance P (SP) are two important neuropeptides synthesised by a subpopulation of peptidergic nociceptors SNs [ 55 ]. They are known to have roles in nociception [ 56 , 57 ], and can modulate bone cells and ECs migration and proliferation [ 41 , 51 ]. In order to investigate their potential role in the effects previously described in the sections above, we first supplemented the ECs medium with different concentrations of CGRP and SP (Fig.…”

“…The antagonists BIBN4096 (for CGRP) and SR140333 (for SP) (Tocris, Bio-Techne) were added directly in ECs culture medium at a concentration of 10 μM each [ 49 – 51 ].…”

Apocynin Treatment Prevents Cardiac Connexin 43 Hemichannels Hyperactivity by Reducing Nitroso-Redox Stress in Mdx Mice

“…In this sense, it is important to note that there are several pathological situations where dysregulation of Cx hemichannels seems to concur with increased activity of (Px) channels [ 46 , 47 , 48 , 49 ]. The interaction between both types of channels is complex, inasmuch in so many cases, blockade of one or the other type of pore-forming hexamers results in abrogation of the overall cellular hyperpermeability, in a non-additive process [ 50 , 51 ]. These observations cannot be explained by eventual un-specificity of pharmacological blockers, since use of specific peptides produces similar effects as using more general chemical blockers as that used in this study; instead, they probably reveal a complex reiterative loop in which hemichannels activity of one type causes opening of the other kind.…”

Aging alters spontaneous and neurotransmitter‐mediated Ca2+ signaling in smooth muscle cells of mouse mesenteric arteries

“…However, increased circulating (serum) CGRP levels with aging (Figure ) may contribute to changes in receptor function in the absence of altered gene expression because chronic exposure to CGRP leads to receptor desensitization, internalization, and degradation . Supporting a non‐CGRP receptor‐mediated pathway for CGRP is a recent study in rat Mas, which found that CGRP released from sensory nerves inhibited endothelial‐mediated vasodilation via pannexin channel opening leading to the inhibition of NO production. In light of elevated serum CGRP with aging (Figure ), this signaling pathway may contribute to the decreased role of the endothelium in affecting SMC Ca 2+ signaling with advanced age.…”