A critical role for elastin signaling in vascular morphogenesis and disease

Abstract

Vascular proliferative diseases such as atherosclerosis and coronary restenosis are leading causes of morbidity and mortality in developed nations. Common features associated with these heterogeneous disorders involve phenotypic modulation and subsequent abnormal proliferation and migration of vascular smooth muscle cells into the arterial lumen, leading to neointimal formation and vascular stenosis. This fibrocellular response has largely been attributed to the release of multiple cytokines and growth factors by inflammatory cells. Previously, we demonstrated that the disruption of the elastin matrix leads to defective arterial morphogenesis. Here, we propose that elastin is a potent autocrine regulator of vascular smooth muscle cell activity and that this regulation is important for preventing fibrocellular pathology. Using vascular smooth muscle cells from mice lacking elastin(Eln-/-), we show that elastin induces actin stress fiber organization, inhibits proliferation, regulates migration and signals via a non-integrin, heterotrimeric G-protein-coupled pathway. In a porcine coronary model of restenosis, the therapeutic delivery of exogenous elastin to injured vessels in vivo significantly reduces neointimal formation. These findings indicate that elastin stabilizes the arterial structure by inducing a quiescent contractile state in vascular smooth muscle cells. Together, this work demonstrates that signaling pathways crucial for arterial morphogenesis can play an important role in the pathogenesis and treatment of vascular disease.

The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

“…It is also known that accumulated dermatan sulfate can activate STAT proteins which increase productions of elastindegrading proteins, i.e., matrix metalloproteinase-12 (MMP-12) and cathepsin S. (Ma et al 2008). Reduction of elastin in myocardial cells, endocardium, and the coronary artery may lead to proliferation of connective tissues, resulting in fibrosis in the ventricular walls, endocardium, and vascular walls (Hinek and Wilson 2000;Karnik et al 2003).…”

Impact of delivery mode of hyaluronan oligomers on elastogenic responses of adult vascular smooth muscle cells

“…Vascular smooth muscle cells (SMCs) typically synthesize elastin as soluble tropoelastin, which is then post-translationally crosslinked by lysyl oxidase into a structural matrix. Vascular elastin allows blood vessels to recoil to their original dimensions during diastole to propel blood forward, and also vitally regulates cell-signaling pathways involved in morphogenesis, injury response, inflammation, and tissue calcification [1][2][3][4][5]. The preservation or restoration of vascular elastin, when it is degraded by disease, or when congenitally absent or malformed, is thus crucial to reinstating vascular homeostasis.…”

Elastic fiber homeostasis requires lysyl oxidase–like 1 protein

“…Our data also show an unexpected, causal link between elastic fiber homeostasis and pelvic prolapse, a clinical condition strongly correlated with both childbirth and advanced age [21][22][23] . Elastin polymer and soluble elastin-derived peptides also have signaling roles in cell adhesion, migration and proliferation 5,24 . Thus, the combination of loss of elastin polymer and accumulation of tropoelastin may have additionally contributed to the histopathologic changes seen in the LOXL1 mutant mice.…”