Sympathetic nerve-derived ATP regulates renal medullary vasa recta diameter via pericyte cells: a role for regulating medullary blood flow?

Abstract

Pericyte cells are now known to be a novel locus of blood flow control, being able to regulate capillary diameter via their unique morphology and expression of contractile proteins. We have previously shown that exogenous ATP causes constriction of vasa recta via renal pericytes, acting at a variety of membrane bound P2 receptors on descending vasa recta (DVR), and therefore may be able to regulate medullary blood flow (MBF). Regulation of MBF is essential for appropriate urine concentration and providing essential oxygen and nutrients to this region of high, and variable, metabolic demand. Various sources of endogenous ATP have been proposed, including from epithelial, endothelial, and red blood cells in response to stimuli such as mechanical stimulation, local acidosis, hypoxia, and exposure to various hormones. Extensive sympathetic innervation of the nephron has previously been shown, however the innervation reported has focused around the proximal and distal tubules, and ascending loop of Henle. We hypothesize that sympathetic nerves are an additional source of ATP acting at renal pericytes and therefore regulate MBF. Using a rat live kidney slice model in combination with video imaging and confocal microscopy techniques we firstly show sympathetic nerves in close proximity to vasa recta pericytes in both the outer and inner medulla. Secondly, we demonstrate pharmacological stimulation of sympathetic nerves in situ (by tyramine) evokes pericyte-mediated vasoconstriction of vasa recta capillaries; inhibited by the application of the P2 receptor antagonist suramin. Lastly, tyramine-evoked vasoconstriction of vasa recta by pericytes is significantly less than ATP-evoked vasoconstriction. Sympathetic innervation may provide an additional level of functional regulation in the renal medulla that is highly localized. It now needs to be determined under which physiological/pathophysiological circumstances that sympathetic innervation of renal pericytes is important.

Pericyte constriction underlies capillary derecruitment during hyperemia in the setting of arterial stenosis

“…Conversely, the proportion of capillary segments dilating to ATP was significantly increased from 24 Ϯ 5% in wild-type to 44 Ϯ 6% in PPD mice (n ϭ 6 -8, P ϭ 0.02). Because ATP-induced capillary constriction depends upon pericytes (8,12,35), these findings are consistent with loss of pericyte function in PPD mice.…”

Structural changes in thestrial blood–labyrinth barrier of aged C57BL/6 mice

“…PC deficiency is known to cause blood barrier breakdown and hypo-perfusion, contributing to tissue pathology and organ disease(Armulik et al 2010; Daneman et al 2010; Crawford et al 2013; Wang et al 2014). PCs also exhibit multi-potent stem cell activity and are found to differentiate into a variety of different cell types, including macrophages, phagocytes, fibroblasts, and smooth muscle cells(Sims 2000; Dore-Duffy et al 2006).…”

Pericytes in Vascular Development

“…Consistent with this idea are observations of pericytes giving rise to vSMCs [21••] and perhaps contributing to arteriogenic remodeling [140] and collateral artery formation. Pericytes have also been reported to respond to vasoactive cues [141], propagate electrical signals within the microcirculation (e.g., via gap junction-mediated conducted vasomotion) [142][143][144], and perform vasomotor functions similar to vSMCs [145][146][147][148][149][150], though passive regulation of vessel diameter by pericytes has also been described [124,151,152]. These studies highlight the need for more innovative models [153,154] and techniques [66,155] to resolve this potential role for capillary pericytes across various tissues and organs.…”