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.
Highlights
Extracellular matrix (ECM) stiffness can directly influence many aspects of physiological and pathological processes, including intestine and lung morphogenesis (Rabelink et al, 2017), blood cell development (Leiva et al, 2018), tumor invasion (Schedin and Keely, 2011) and vascular aging (Lacolley et al, 2017)
The main component in areas of hyperplasia was vascular smooth muscle cells (VSMCs), and there was a large amount of collagen in the neointima, which may affect the mechanical properties of the injured artery
Col8a2 was mostly located in the nucleus (Supplementary Figure 3B), which was different from the traditional understanding of VSMCs (Stephan et al, 2004; Adiguzel et al, 2006). These results suggest that platelet-derived extracellular vesicles (pEVs)-induced VSMCs produce and secrete Collagen type VIII alpha chain (Col8a1), which may contribute to ECM remodeling during vascular intimal injury
Summary
Extracellular matrix (ECM) stiffness can directly influence many aspects of physiological and pathological processes, including intestine and lung morphogenesis (Rabelink et al, 2017), blood cell development (Leiva et al, 2018), tumor invasion (Schedin and Keely, 2011) and vascular aging (Lacolley et al, 2017). ECM remodeling, including increasing collagen deposition, cross-linking collagen, and breaking down elastic laminae, affects arterial stiffness and promotes the proliferation of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) (Thenappan et al, 2018). In atherosclerosis, the elastic modulus of the thoracic aorta reaches 15 kPa in comparison with 5 kPa in normal mice and increases VSMC proliferation, apoptosis and osteochondrogenic transformation (Xie et al, 2018). Arterial stiffness could become an important marker to characterize vascular damage (Duprez and Cohn, 2007)
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