Signals of the Neuropilin-1–MET Axis and Cues of Mechanical Force Exertion Converge to Elicit Inflammatory Activation in Coherent Endothelial Cells

Abstract

The neuropilin-1 (NRP1)-MET signaling axis regulates the motility of individual endothelial cells (ECs). It is unknown how this signaling pathway affects the endothelial barrier in coherent ECs forming a tight monolayer. We hypothesized that it is involved both in modulation of the endothelial barrier and in EC activation. To investigate the role of NRP1-MET signaling in inflammatory processes (e.g., systemic inflammatory response syndrome [SIRS] or snakebite-induced SIRS-like conditions), we employed the C-type lectin-related protein rhodocetin-ab (RCab) as a specific trigger of this signal axis in ECs in vitro. In coherent HUVECs, RCab reinforced the actin cytoskeleton and increased cell stiffness, thus favoring vascular endothelial cadherin-mediated transmission of intercellular forces. Increased cell stiffness was associated with enhanced activation of RhoA and nuclear translocation of NF-kB. Simultaneously, RCab-triggered signaling via the NRP1-MET axis increased EC monolayer permeability, induced transcription of proinflammatory genes such as ICAM-1 and, consequently, leukocyte tethering. The RCab-induced transcriptome differed from that induced by hepatocyte growth factor, although in both cases the same tyrosine kinase, MET, was involved. This was due to RCab-mediated recruitment of the MET coreceptor NRP1 and additional Rho-mediated activation of the actomyosin system. RCab induced similar transcriptional and cellular changes if external shear forces were applied. These data highlight the modulatory role of NRP1 as MET coreceptor, and they explain how some snake venoms induce SIRS-like conditions. Additionally, this study demonstrates that inflammatory activation of coherent ECs is triggered by converging signals that are induced by NRP1-MET signaling and influenced by intercellular forces.

Structurally Robust and Functionally Highly Versatile—C-Type Lectin (-Related) Proteins in Snake Venoms

“…This elicits several pleiotropic effects in endothelial cells, among them the rearrangement of integrins and adhesomes, as well as of the adhesome-anchored actin cytoskeleton [151]. In a monolayer of coherent endothelial cells, rhodocetin-αβ induces their activation and consequently augments diapedesis of myeloid immune cells [201]. In two animal tumour models, this SV-CLRP does not primarily influence endothelial cells in normal vessels because of the inaccessibility of blood-borne rhodocetin-αβ to the basolaterally expressed neuropilin-1.…”

Effect of Butylphthalide combined with Oxiracetam on cognitive function, Intellectual recovery and serum inflammatory factors in patients with cognitive impairment after cerebral infarction

“… 24 Cerebral ischemia can lead to the activation of endothelial cells, which can accelerate the release of IL-6, TNF-α and other inflammatory factors. 25 Kamnaksh et al 26 have documented in their research that increased expression levels of IL-6 and TNF-α in the cerebrospinal fluid would indicate higher severity of the condition in patients with vascular cognitive impairment. Simultaneously, hippocampal gray matter volume is an important index to determine the severity of vascular cognitive impairment.…”

Efficacy and association of hyperbaric oxygen therapy combined with butylphthalide and oxiracetam with serum levels of inflammatory markers in vascular cognitive impairment after acute ischemic stroke

“…25 Cerebral ischemia can activate endothelial cells and accelerate the release of IL-6 and TNF-α. 26 Kamnaksh et al 27 showed that VCI worsened with the increase in IL-6 and TNF-α expression in cerebrospinal fluid; a higher plasma level of IL-6 indicated smaller hippocampal gray matter volume, a marker of severity in VCI patients. In other words, inflammatory responses probably affect the hippocampal gray matter via the IL-6 pathway.…”