Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration

Abstract

Fibulin (fbln)-5 is an elastin-binding protein required for assembly and organization of elastic fibers. To examine the potential role of fbln-5 in vascular remodeling and neointima formation, we induced vascular injury by carotid artery ligation in fbln-5 ؊/؊ mice. Mutant mice displayed an exaggerated vascular remodeling response that was accompanied by severe neointima formation with thickened adventitia. These abnormalities were not observed in elastin ؉/؊ mice that exhibited a comparable reduction of vessel extensibility to fbln-5 ؊/؊ mice. Thus, the severe remodeling response could not be attributed to altered extensibility of the vessel wall alone. Vascular smooth muscle cells cultured from fbln-5 ؊/؊ mice displayed enhanced proliferative and migratory responses to mitogenic stimulation relative to wild-type cells, and these responses were inhibited by overexpression of fbln-5. These findings demonstrate the importance of the elastic laminae in vascular injury, and reveal an unexpected role of fbln-5 as an inhibitor of vascular smooth muscle cell proliferation and migration.elastic fibers ͉ extracellular matrix ͉ neointima ͉ elastin V ascular obstructive abnormalities, such as atherosclerosis and restenosis after percutaneous coronary intervention, are triggered by damage to the vessel wall, initiating a series of biological responses, including up-regulation of adhesion molecules, recruitment of inflammatory cells, secretion of cytokines, and activation of smooth muscle cells (SMCs). Activated SMCs secrete growth factors, extracellular matrix proteins, and matrix proteases, thereby altering the microenvironment of the injured vessel wall. Much attention has focused on the signaling pathways responsible for the proliferation and migration of SMCs associated with vascular obstruction, but relatively little is known of the potential contributions of extracellular matrix proteins to these processes (reviewed in ref. 1).Structural changes of the vessel wall induced by mechanical force or enzymatic digestion also influence the development of vascular obstructive disease (2, 3). The elastic lamina plays a critical role in maintaining the integrity of the vessel wall. Rupture of the external elastic lamina (EEL) is a more potent stimulus for neointima formation than injury involving the internal elastic lamina (IEL) alone after coronary artery stent-induced injury (4). In addition, exposure of the adventitia to the blood lumen by disruption of the EEL during percutaneous angioplasty increases the activation of adventitial myofibroblasts, leading to adventitial fibrosis that eventually constricts the vessel wall (5).The perception of the elastic lamina (or elastic fibers) as the sole structural component of the vessel wall was recently challenged by the view that elastic fibers actively modulate intercellular signaling. Elastin (eln), a major component of the elastic fibers in the arterial wall, inhibits proliferation of SMCs (6). Eln is secreted as a tropoelastin monomer and subsequently undergoes cross-linking t...

Loss of fibulin-5 binding to β1 integrins inhibits tumor growth by increasing the level of ROS

“…Chronic increases in ROS production have been shown to contribute to the onset of certain diseases that are also connected to the loss of Fbln5 expression, such as macular degeneration and cardiovascular disease (Bonomini et al, 2008;Lotery et al, 2006;Spencer et al, 2005;Takahashi et al, 2004). Our data would suggest that the loss of Fbln5 promotes the progression of these diseases by causing an increase in ROS production.…”

Endothelial and Smooth Muscle-derived Neuropilin-like Protein Regulates Platelet-derived Growth Factor Signaling in Human Vascular Smooth Muscle Cells by Modulating Receptor Ubiquitination

“…Other regulators of VSMC proliferation and migration and neointima formation have been described. Similar to ESDN, fibulin-5 is minimally expressed in normal arteries, is up-regulated in conjunction with neointima formation in remodeling arteries, and negatively regulates VSMC proliferation and migration (25). Integrins, such as ␣v␤3 (26) and ␣7␤1 (27,28), are induced and modulate VSMC proliferation and migration in vascular remodeling at multiple levels, including potentiation of ligand-dependent and -independent growth factor receptor signaling (29) through matrix engagement.…”

Placental Defects in α7 Integrin Null Mice

“…VSMC differentiation is associated with the expression of specific smooth muscle cell markers including tropomyosin and smooth muscle myosin heavy chain [41]. VSMCs are known to switch to a less differentiated state after vascular damage [42].…”