Endothelial C-Type Natriuretic Peptide Acts on Pericytes to Regulate Microcirculatory Flow and Blood Pressure

Abstract

-Peripheral vascular resistance has a major impact on arterial blood pressure levels. Endothelial C-type natriuretic peptide (CNP) participates in the local regulation of vascular tone but the target cells remain controversial. The cGMP-producing guanylyl cyclase-B (GC-B) receptor for CNP is expressed in vascular smooth muscle cells (VSMC). However, whereas endothelial cell-specific CNP knockout mice are hypertensive, mice with deletion of GC-B in VSMC have unaltered blood pressure. -We analyzed whether the vasodilating response to CNP changes along the vascular tree, i.e. whether the GC-B receptor is expressed in microvascular types of cells. Mice with a floxed GC-B () gene were interbred with or lines to develop mice lacking GC-B in endothelial cells or in precapillary arteriolar SMC and capillary pericytes. Intravital microscopy, (non)invasive hemodynamics, fluorescence energy transfer studies of pericyte's cAMP levels and renal physiology were combined to dissect whether and how CNP/GC-B/cGMP signaling modulates microcirculatory tone and blood pressure. -Intravital microscopy studies revealed that the vasodilatatory effect of CNP increases towards small-diameter arterioles and capillaries. Consistently, CNP did not prevent endothelin-1-induced acute constrictions of proximal arterioles but fully reversed endothelin effects in precapillary arterioles and capillaries. Here, the GC-B receptor is expressed both in endothelial and mural cells, i.e. in pericytes. Notably, the vasodilatatory effects of CNP were preserved in mice with endothelial GC-B deletion but abolished in mice lacking GC-B in microcirculatory SMC and pericytes. CNP, via GC-B/cGMP signaling modulates two signaling cascades in pericytes: it activates cGMP-dependent protein kinase I to phosphorylate downstream targets such as the cytoskeleton-associated vasodilator activated phosphoprotein; and it inhibits phosphodiesterase 3A, thereby enhancing pericyte's cAMP levels. Ultimately these pathways prevent endothelin-induced increases of pericyte calcium levels and pericyte contraction. Mice with deletion of GC-B in microcirculatory SMC and pericytes have elevated peripheral resistance and chronic arterial hypertension without a change in renal function. -Our studies indicate that endothelial CNP regulates distal arteriolar and capillary blood flow. CNP-induced GC-B/cGMP signaling in microvascular SMC and pericytes is essential for the maintenance of normal microvascular resistance and blood pressure.

Metabolic‐vascular coupling in skeletal muscle: A potential role for capillary pericytes?

“…In this review, we have highlighted the emerging evidence for pericyte‐mediated regulation of capillary blood flow across various organs within the body. While the concept that pericytes actively regulate capillary blood flow in muscle is in its relative infancy, current studies suggest that (a) pericytes are present around skeletal muscle capillaries (Figure ;); (b) skeletal muscle pericytes have the capacity to regulate capillary diameter and (c) degeneration of capillary pericytes occurs in skeletal muscle during type 2 diabetes . Based on the emerging repertoire of pericyte functions in other organs, the immediate need in skeletal muscle research is to (a) determine whether skeletal muscle pericytes are able to actively regulate capillary tone in response to circulating and metabolic factors; (b) determine how pericyte loss from the microvasculature impacts muscle function and microvascular responses; and (c) characterize the anatomical locations of pericytes in skeletal muscle and determine whether this differs between different muscle fibre types.…”

“…Importantly, studies have shown that insulin mediates its vascular actions through nitric oxide and endothelin‐1 . Moreover, Spiranac et al recently reported that endothelin‐1 provokes strong and stable contraction of individual capillary pericytes in mouse cremaster muscle in vivo via a Ca 2+ ‐mediated mechanism . Coupled with the knowledge that muscle capillaries are almost completely covered by pericytes (Figure C), that insulin can act directly on pericytes in other organs, and that pericytes are lost from skeletal muscle capillaries in type 2 diabetes, it is tempting to speculate that pericytes may contribute to insulin's actions on the muscle microvasculature and that these may be lost in insulin resistance.…”

“…Given the evidence summarized above and the anatomical organization of the muscle vasculature, it stands to reasons that arteriolar constriction/dilation is a major determinant of vascular resistance and hence capillary perfusion in muscle during exercise . However, given the presence of pericytes around skeletal muscle capillaries, and the emerging evidence for pericyte contraction and dilation, capillaries (via pericyte actions) are able to alter capillary blood flow and/or blood content independently from, or in conjunction with arterioles to determine nutrient delivery to skeletal muscle fibres to control local metabolism . While these subtle capillary flow oscillations may not be easily distinguishable during high‐intensity exercise, they may be identifiable at lower work rates that do not increase bulk flow or in instances where muscle capillary perfusion is increased independent of muscle contraction .…”

“…Intriguingly, while the presence of pericytes around capillaries in skeletal muscle has been documented for over 40 years, to our knowledge only two recent studies have reported that skeletal muscle pericytes can actively modulate capillary diameter. The first utilised intravital microscopy of the cremaster muscle microcirculation to demonstrate pericyte responsiveness to endothelin‐1 . The second study utilised two‐photon microscopy to demonstrate that hyperaemia‐induced changes in capillary diameter in muscle occurred preferentially in pericyte‐covered capillary segments and that this vasodilator response was reduced in states of pericyte depletion .…”

Host Peptidic Hormones Affecting Bacterial Biofilm Formation and Virulence

“…1). In addition, in human cells, CNP was shown to bind both on the natriuretic peptide receptor (NPR) subtypes B (NPR-B) and C (NPR-C) [72], regulating cGMP and cAMP intracellular concentrations, respectively [72, 73]. Altogether, these data suggested that a putative bacterial CNP sensor could be present in P. aeruginosa .…”