Does a Message from the Matrix Raise Your Blood Pressure?

Abstract

The pathogenesis of hypertension--a risk factor for heart disease, kidney disease, and stroke--is complex and poorly understood (see Raman and Cobb). Zacchigna et al. found that mice lacking elastin microfibril interface-located protein 1 (Emilin1), a secreted extracellular matrix protein expressed in the cardiovascular system, had high blood pressure in conjunction with decreased blood vessel diameter and increased peripheral resistance. Emilin1 contains a cysteine-rich domain, as do some proteins involved in regulation of growth factor signaling, leading the authors to investigate the relation between Emilin1 and transforming growth factor-β (TGF-β), which plays a critical role in vascular development and pathophysiology. Experiments in Xenopus embryos and mammalian cell culture systems indicated that Emilin1 acts through the cysteine-rich EMI domain to block TGF-β signaling. Emilin1 acted upstream of receptor activation and failed to block ligand-receptor binding or signaling in response to mature TGF-β1. Rather, Emilin1 bound to proTGF-β1, preventing its proteolytic processing and the production of biologically active TGF-β1. Emilin1 gain- and loss-of-function experiments in which "stimulator" cells (which produced TGF-β) were mixed with "responder" cells (which expressed TGF-β reporters), and experiments involving nonsecretable Emilin1, indicated that Emilin1 acted extracellularly. TGF-β signaling (nuclear staining for phosphorylated Smad2 and expression of a TGF-β reporter) was enhanced in the aortic wall of the mice lacking Emilin1, and inactivation of one TGF-β1 allele in Emilin1 knockout mice restored normal blood vessel diameter and blood pressure. Thus, the authors conclude that Emilin1 acts to regulate blood pressure by modulating TGF-β processing and thus the availability of the biologically active form. L. Zacchigna, C. Vecchione, A. Notte, M. Cordenonsi, S. Dupont, S. Maretto, G. Cifelli, A. Ferrari, A. Maffei, C. Fabbro, P. Braghetta, G. Marino, G. Selvetella, A. Aretini, C. Colonnese, U. Bettarini, G. Russo, S. Soligo, M. Adorno, P. Bonaldo, D. Volpin, S. Piccolo, G. Lembo, G. M. Bressan, Emilin1 links TGF-β maturation to blood pressure homeostasis. Cell 124 , 929-942 (2006). [Online Journal] M. Raman, M. H. Cobb, TGF-β regulation by Emilin1: New links in the etiology of hypertension. Cell 124 , 893-895 (2006). [Online Journal]