β1-Integrins Mediate Enhancement of Airway Smooth Muscle Proliferation by Collagen and Fibronectin

Abstract

Airway smooth muscle (ASM) accumulation and enrichment of the extracellular matrix (ECM) with type I collagen and fibronectin are major pathologic features of airway remodeling in asthma. These ECM components confer enhanced ASM proliferation in vitro, but a requirement for specific integrin ECM receptors has not been examined. Here, we examined the mitogen platelet-derived growth factor (PDGF)-BB on beta1-integrin expression on human ASM cells cultured on these ECM substrates and defined the involvement of specific integrins in cell attachment and proliferation using integrin-neutralizing antibodies. PDGF-BB-dependent proliferation was enhanced two- to threefold by monomeric type I collagen or fibronectin and to a lesser extent by vitronectin; other interstitial ECM components (fibrillar type I and III collagen and tenascin-C) had no effect. Except for increased alpha3 expression induced by PDGF-BB and monomeric type I collagen or fibronectin, alpha1, alpha2, alpha4, alpha5, alphav, and alphavbeta3 integrins were unchanged compared with unstimulated cells on plastic. Blocking antibodies revealed alpha2beta1- and alphavbeta3-mediated attachment to monomeric type I collagen, whereas attachment to fibronectin required alpha5beta1. In contrast, enhancement of PDGF-BB-dependent proliferation by either monomeric type I collagen or fibronectin required alpha2beta1, alpha4beta1, and alpha5beta1 integrins. These data suggest multiple beta1-integrins regulate enhanced ASM proliferative responses.

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

“…2D). These data indicate that the effect of Mfge8 on ASM contraction is dependent on the integrin-binding and discoidin [32][33][34][35]. Therefore, the potential integrin receptors for Mfge8 in ASM are αvβ3, αvβ5, αvβ1, or α8β1.…”

Substrate-induced phenotypic switches of human smooth muscle cells: anin vitrostudy of in-stent restenosis activation pathways

“…These functions are indeed controlled by specific adhesion receptors that serve as a transmembrane link between the ECM and the cytoskeleton [18]. As a consequence of this link, the ECM can control cell activity, while the cell can affect the remodelling of the ECM [18][19][20][21][22][23][24]. The most important adhesion receptors in this process are the integrins [18].…”

“…In arterial SMCs, the b1 subunit of these integrins appears to be activated to enhance its affinity towards ECM ligands [21]. For these reasons, b1-integrin seems to play a fundamental role in the control of the SMC contractile phenotype and for the reorganization of the collagen matrix [18,21,23].…”

“…Conversely, in the case of injuries to the artery wall, this subunit may become deactivated, thus allowing the switch of the SMCs from a contractile to a migratory and proliferative phenotype [23]. Other studies such as integrin blocking have been considered but not performed in this study as they would have led to artefacts in cell morphology whilst offering no significant insight into cell behaviour.…”

siRNA silencing reveals role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration

“…The mechanism underlying the effect of VCAM-1 on SMC proliferation is unknown. However, it is known that VCAM-1 interacts with the integrin α 4 β 1 (very lateacting antigen 4), which is expressed on the surface of SMC [9], and β-integrins mediate the enhancement of smooth muscle proliferation by collagen and fibronectin [23]. Thus, it is possible that the integrin α 4 β 1 -VCAM-1 interaction enhances the proliferative response of SMC to stimuli like collagen.…”