Abstract-Mechanotransduction represents an integral part of vascular homeostasis and contributes to vascular lesion formation. Previously, we demonstrated a mechanosensitive activation of phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt) resulting in p27 Kip1 transcriptional downregulation and cell cycle entry of vascular smooth muscle cells (VSMC). In this study, we further elucidated the signaling from outside-in toward PI3-K/Akt in vitro and in an in vivo model of elevated tensile force. When VSMC were subjected to cyclic stretch (0.5 Hz at 125% resting length), PI3-K, Akt, and Src kinases were found activated. Disrupting caveolar structures with -cyclodextrin or transfection of VSMC with caveolin-1 antisense oligonucleotides (ODN) prevented PI3-K and Akt activation and cell cycle entry. Furthermore, PI3-K and Akt were resistant to activation when Src kinases were inhibited pharmacologically or by overexpression of a kinase-dead c-Src mutant. ␣ V  3 integrins were identified to colocalize with PI3-K/caveolin-1 complexes, and blockade of ␣ V  3 integrins prevented Akt activation. The central role of caveolin-1 in mechanotransduction was further examined in an in vivo model of elevated tensile force. Interposition of wild-type (WT) jugular veins into WT carotid arteries resulted in a rapid Akt activation within the veins that was almost abolished when veins of caveolin-1 knockout (KO) mice were used. Furthermore, late neointima formation within the KO veins was significantly reduced. Our study provides evidence that PI3-K/Akt is critically involved in mechanotransduction of VSMC in vitro and within the vasculature in vivo. Furthermore, caveolin-1 is essential for the integrin-mediated activation of PI3-K/Akt. (Circ Res. 2005;96:635-642.) Key Words: remodeling Ⅲ muscle, smooth Ⅲ signal transduction Ⅲ stress Ⅲ vasculature I t is currently recognized that the machinery governing the cell cycle regulates multiple cellular functions in the cardiovascular system, thereby maintaining the homeostasis of the vasculature and allowing its adaptation to acute and chronic changes. Besides organizing cellular proliferation, the cell cycle is involved in migration, apoptosis, and hypertrophy. 1 One of the major constituents of the blood vessel wall responsible for the maintenance of vessel structures and functions are vascular smooth muscle cells (VSMCs). In the vasculature, VSMCs are constantly exposed to alternating mechanical forces. Under normal tensile stress, VSMCs are relatively insensitive to mitogens. During altered mechanical stress (eg, high blood pressure), however, VSMCs upregulate protein synthesis in response to growth factors, dedifferentiate, and increase their proliferative rate, resulting in medial hypertrophy and intimal hyperplasia. 2 Whereas the commonly accepted "response to injury" hypothesis suggests that growth factors are locally released, thereby initiating cell cycle entry and progression of vascular cells, the signaling pathways arising solely from mechanical force have just partially c...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.