RT Journal Article
SR Electronic
T1 Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP signaling pathway in the remodeling of blood vessels
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 814533
DO 10.1101/814533
A1 Yoshito Yamashiro
A1 Bui Quoc Thang
A1 Karina Ramirez
A1 Seung Jae Shin
A1 Tomohiro Kohata
A1 Shigeaki Ohata
A1 Tram Anh Vu Nguyen
A1 Sumio Ohtsuki
A1 Kazuaki Nagayama
A1 Hiromi Yanagisawa
YR 2019
UL http://biorxiv.org/content/early/2019/10/22/814533.abstract
AB Rationale The extracellular matrix (ECM) initiates mechanical cues and transduces intracellular signaling through matrix-cell interactions. In the blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from ECM and how they coordinate with a mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood.Objective The aim of this study was to elucidate the crucial mediator(s) and molecular signaling pathway(s) involved in matrix mechanotransduction during remodeling of the vessel wall.Methods and Results We performed secretome analysis using rat vascular smooth muscle cells (SMCs) under cyclic stretch and examined matrix-cell interactions and cell behavior. We found that the matricellular protein thrombospondin-1 (Thbs1) was secreted upon cyclic stretch and bound to integrin αvβ1, thereby recruiting vinculin and establishing focal adhesions. RNA-sequence (RNA-seq) analysis revealed that deletion of Thbs1 in vitro markedly affected the target gene expression of Yes-associated protein (YAP). Consistently, we found that Thbs1 promotes nuclear shuttling of YAP in response to cyclic stretch, which depends on the small GTPase Rap2 and Hippo pathway, and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload by transverse aortic constriction (TAC), whereas it suppressed neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall.Conclusions Thbs1 serves as a mechanical stress-triggered extracellular mediator of mechanotransduction that acts via integrin αvβ1 to establish focal adhesions and promotes nuclear shuttling of YAP. We thus propose a novel mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.Subject codesVascular DiseaseGenetically Altered and Transgenic ModelsVascular BiologyCell Signaling/Signal TransductionECMExtracellular matrixpPhosphorylatedSMCSmooth muscle cellECEndothelial cellFAsFocal adhesionsYAPYes-associated proteinThbs1Thrombospondin-1FAKFocal adhesion kinaseBFABrefeldin AIPAIngenuity Pathway AnalysisPLAProximity Ligation AssayAFMAtomic force microscopyRNA-seqRNA sequencingDAPI4’, 6-diamidino-2-phenylindoleCMConditioned mediaTACTransverse aortic constrictionIELInternal elastic lamellaLCALeft carotid arteryCTGFConnective tissue growth factorGAPDHGlyceraldehyde-3-phosphate dehydrogenase