Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling

Abstract

The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix–cell interactions. In 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 the ECM and their interaction with the mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood. Here, we identified the matricellular protein thrombospondin-1 (Thbs1) as an extracellular mediator of matrix mechanotransduction that acts via integrin αvβ1 to establish focal adhesions and promotes nuclear shuttling of Yes-associated protein (YAP) in response to high strain of cyclic stretch. Thbs1-mediated YAP activation 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 β1/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload and inhibition of neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall. We thus propose a mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.

ADAM (a Disintegrin and Metalloproteinase) 15 Deficiency Exacerbates Ang II (Angiotensin II)–Induced Aortic Remodeling Leading to Abdominal Aortic Aneurysm

“…THBS1 binds to integrin αvβ1 to form focal adhesion, subsequently mediating nuclear shuttling of YAP (Yes-associated protein), thereby linking mechanotransduction to vascular remodeling. 45 THBS1-mediated apoptosis of SMCs could be through activation of the integrin complex, through association with CD47, as reported in fibroblasts, 46 or other membrane-associated proteins. AoSMCs are critical for renewal of the aortic ECM proteins and for the aortic contractile function.…”

“…The increased apoptosis could be through activation of the integrin-αvβ1-CD47 complex as we observed elevated integrin-αv and integrin-β1 levels in Ang II–infused Adam15 −/− aorta (Figure VI in the Data Supplement ), and this mechanism has been linked to THBS1-mediated SMC function and apoptosis. 45 , 46 Cofilin activity (total-to-phosphorylated ratio) was increased, whereas cell proliferation pathways (ERK1/2 and Akt) were suppressed in Adam15 −/− -AoSMCs following THBS1 treatment (Figure 7 C). rhTHBS1 did not increase cofilin activity in WT-AoSMCs, suggesting that ADAM15 deficiency may be a requirement for THBS1-mediated cofilin activation and the subsequent depolymerization of F-actin to G-actin in AoSMCs.…”

Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression

“…In addition to common integrin ligands such as collagens and fibronectin, an ECM proteoglycan, Agrin, also act as an extracellular mediator of matrix mechanotransduction to regulate YAP/TAZ via integrins, its specific membrane receptor LRP4, and the actin cytoskeleton ( Chakraborty et al, 2017 ; Chakraborty et al, 2020 ). Similarly, matricellular protein thrombospondin-1, acts through integrin-1 and the Hippo pathway, but not actin cytoskeleton, to activate YAP/TAZ ( Yamashiro et al, 2020 ). Besides signaling through integrin/focal adhesion, plasma membrane protein Caveolin-1 (CAV-1) also play a critical role in mechanoregulation of YAP/TAZ ( Moreno-Vicente et al, 2018 ).…”

C9orf72- derived proline:arginine poly-dipeptides disturb cytoskeletal architecture

“…Cyclic stretch was performed using a uniaxial cell stretch system (Central Workshop Tsukuba University) as described in an existing study [Yamashiro et al, 2020]. The rat vascular SMCs were plated on silicon elastomer bottomed culture plates (SC4Ha, Menicon Life Science) coated with cell attachment factor containing gelatin (Thermo Fisher Scientific, S006100) and subjected to cyclic stretch with a frequency of 1.0 Hz (60 cycles/min) and 20% strain for six hours.…”