Platelet-Derived Extracellular Vesicles Increase Col8a1 Secretion and Vascular Stiffness in Intimal Injury

Abstract

The arterial mechanical microenvironment, including stiffness, is a crucial pathophysiological feature of vascular remodeling, such as neointimal hyperplasia after carotid endarterectomy and balloon dilatation surgeries. In this study, we examined changes in neointimal stiffness in a Sprague-Dawley rat carotid artery intimal injury model and revealed that extracellular matrix (ECM) secretion and vascular stiffness were increased. Once the endothelial layer is damaged in vivo, activated platelets adhere to the intima and may secrete platelet-derived extracellular vesicles (pEVs) and communicate with vascular smooth muscle cells (VSMCs). In vitro, pEVs stimulated VSMCs to promote collagen secretion and cell adhesion. MRNA sequencing analysis of a carotid artery intimal injury model showed that ECM factors, including col8a1, col8a2, col12a1, and elastin, were upregulated. Subsequently, ingenuity pathway analysis (IPA) was used to examine the possible signaling pathways involved in the formation of ECM, of which the Akt pathway played a central role. In vitro, pEVs activated Akt signaling through the PIP3 pathway and induced the production of Col8a1. MicroRNA (miR) sequencing of pEVs released from activated platelets revealed that 14 of the top 30 miRs in pEVs targeted PTEN, which could promote the activation of the Akt pathway. Further research showed that the most abundant miR targeting PTEN was miR-92a-3p, which promoted Col8a1 expression. Interestingly, knockdown of Col8a1 expression in vivo abrogated the increase in carotid artery stiffness and simultaneously increased the degree of neointimal hyperplasia. Our results revealed that pEVs may deliver miR-92a-3p to VSMCs to induce the production and secretion of Col8a1 via the PTEN/PIP3/Akt pathway, subsequently increasing vascular stiffness. Therefore, pEVs and key molecules may be potential therapeutic targets for treating neointimal hyperplasia.

Endothelial-derived extracellular microRNA-92a promotes arterial stiffness by regulating phenotype changes of vascular smooth muscle cells

“…4 E). Given that miR-92a level is significantly increased in carotid arteries after intima injury 13 , we analyzed RNA-seq data (GSE164050) from carotid arteries. Consistent with our results, marker genes of the contractile phenotype of VSMCs were downregulated, and those of the proliferative phenotype were upregulated in carotid arteries (Fig.…”

“…Upon vascular damage, activated platelets adhere to the intima, then secrete platelet-derived EVs. These miR-92a-containing EVs, when transported to VSMCs, can induce Col8a1, which augments vascular stiffness 13 . Our results showed that Ang II increased miR-92a level in ECs, which resulted in EC dysfunction.…”

“…Increasing evidence indicates that extracellular miRNAs can serve as biomarkers for the diagnosis, treatment, and prognosis of cardiovascular diseases [8][9][10] . In addition, miRNAs can function as second messengers mediating cellular communication between ECs and neighboring cells within the vascular wall [11][12][13] . Elevated miR-92a level in the cardiovascular system is linked to the pathophysiology of cardiovascular diseases [14][15][16] .…”

Treated dentin matrix induces odontogenic differentiation of dental pulp stem cells via regulation of Wnt/β-catenin signaling

“…3 E. We found that the expression of mineralization markers such as BGN, COL11A1 , and COL10A1 were significantly increased [ [30] , [31] , [32] , [33] ]. Similarly, the expression of vascular and neurological differentiation markers such as COL8A2 and ANKRD1 also increased to a certain extent [ 34 , 35 ]. Furthermore, these results demonstrated that the odontogenesis of hDPSCs was promoted by TDM induction.…”

Complement facilitates developmental microglial pruning of astrocyte and vascular networks

“…Astrocytes are known to secrete ECM proteins that provide a substrate for endothelial tip cell migration and the formation of superficial retinal vasculature [12,14,63,15]. Defect or changes in ECM molecular composition could alter vascular growth and vascular matrix integrity [64,14,65]. As prior report indicate a role for C3a-C3aR axis in regulating proteases mediated ECM remodeling [66], enrichment of ECM related genes in C3 and C3aR deficient retinas suggest a possible defect in remodeling of ECM components involved in angiogenesis [64,14,65].…”