Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury

Abstract

Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC–pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC–pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO–sGC) is impaired in ALI. Indeed, stimulating the NO–sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC–pericyte interactions. Collectively, our data demonstrate that impaired NO–sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI.

Pericyte signaling via soluble guanylate cyclase shapes the vascular niche and microenvironment of tumors

“…3B ). These results align with previous studies showing that sGC is required to suppress the expression of inflammatory cytokines in the pericytes of the lung and liver (Flores-Costa et al, 2018 ; He et al, 2023 ; Yang et al, 2021 ). The downregulated genes in pericytes were involved in an extracellular matrix organization and cell–matrix adhesion (Fig.…”

“…Previous studies have demonstrated that the NO receptor sGC is specifically expressed in the pericytes of healthy vessels in various organs, including the brain, retina, lung, liver, and muscle, with diverse functions ranging from maintaining vascular integrity to contributing to tissue fibrosis (Bettaga et al, 2015 ; Friebe and Englert, 2022 ; Fukutani et al, 2009 ; He et al, 2023 ; He et al, 2016 ; Yang et al, 2021 ). However, the expression pattern and function of sGC in tumors have not been characterized.…”

“…The role of eNOS-NO-sGC signaling in regulating vSMCs relaxation and vascular tone is widely recognized (Rees et al, 1989 ; Stasch et al, 2011 ). However, the expression of sGC in pericytes has only recently been identified (Bettaga et al, 2015 ; Friebe and Englert, 2022 ; Fukutani et al, 2009 ; He et al, 2023 ; He et al, 2016 ; Yang et al, 2021 ). In the current study, we have demonstrated the specific expression of sGC in tumor pericytes.…”

“…NO-sGC signaling is recognized as the key signaling mediating the crosstalk between ECs and vascular smooth muscle cells for vascular tone regulation (Rees et al, 1989 ; Stasch et al, 2011 ). The expression of sGC in pericytes has only recently been reported (Bettaga et al, 2015 ; Friebe and Englert, 2022 ; Fukutani et al, 2009 ; He et al, 2023 ; He et al, 2016 ; Yang et al, 2021 ); nevertheless, its exact role in pericytes remains incompletely elucidated. Our recent findings revealed that NO-sGC represents one of the most significantly downregulated EC–pericyte crosstalk in the lung, primarily due to the marked decrease in sGC levels following an inflammatory challenge.…”

“…This leads to pericyte detachment and increased vascular permeability. Moreover, pharmacological activation of sGC inhibits cytoskeleton reorganization and suppresses pericyte detachment, thereby preserving pericyte ensheathment and restoring vascular integrity (He et al, 2023 ). Notably, previous research demonstrated that EC-expressed eNOS and its product NO play an essential role in pericyte recruitment during tumor development (Kashiwagi et al, 2005 ).…”