Larger Pipe, Lower Resistance

Abstract

STKE The pathogenesis of hypertension—a risk factor for heart disease, kidney disease, and stroke—is complex and poorly understood. Zacchigna et al. find 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 other proteins involved in the regulation of growth factor signaling, leading the authors to investigate the relationship between Emilin1 and transforming growth factor-β (TGF-β), which plays a critical role in vascular development and pathophysiology. Emilin1 blocked TGF-β signaling upstream of receptor activation and did not interfere with 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. TGF-β signaling 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. — EMA Cell 124 , 929 (2006).