Vascular Matrix Metalloproteinase-2 Cleaves Big Endothelin-1 Yielding a Novel Vasoconstrictor

Abstract

Abstract-Matrix metalloproteinase-2 (MMP-2, gelatinase A) and its tissue inhibitor (TIMP-2) are mainly known for their roles in the (patho)physiological remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. A mechanism of action of MMP-2 is the proteolytic breakdown of specific extracellular matrix proteins. The amino acid sequences in interstitial collagen (Gly-Leu/Ile) and laminin-5 (Ala-Leu) that are cleaved by MMP-2 are homologous to a region (Gly 32 -Leu 33 ) within human big endothelin-1[1 to 38] (big ET-1). Big ET-1 requires cleavage to an active form to produce vasoconstriction. We tested the hypothesis that vascular MMP-2 can cleave big ET-1, thus generating a vasoconstrictor peptide. In perfused rat mesenteric arteries with an intact endothelium, inhibition of vascular MMP-2 with TIMP-2 reduced (by 16.2Ϯ4.2%) the vasoconstrictor effects of big ET-1 (50 pmol). However, when the endothelium was mechanically removed, TIMP-2 abolished (Ͼ90%) the vasoconstriction of big ET-1, and this effect was mimicked by an anti-MMP-2 antibody. Incubation of big ET-1 with recombinant human MMP-2 resulted in the specific cleavage of the Gly 32 -Leu 33 bond of big ET-1. Moreover, the resultant peptide ET-1[1 to 32] exerted greater vasoconstrictor effects than big ET-1. We conclude that vascular MMP-2 contributes to the vasoconstrictor effects of big ET-1 by cleaving big ET-1 to yield a novel and potent vasoconstrictor, ET-1[1 to 32]. These data implicate, for the first time, the endogenous MMP-2/TIMP-2 system in the regulation of vascular reactivity. (Circ Res. 1999;85:906-911.)

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

“…19,20,58 Our data demonstrate that active MMP-1 is also a regulator of vascular reactivity. Therefore, increasing levels of MMP-1 in preeclampsia seem to be central to the hypertensive disorder observed in these women.…”

“…19,20,36 To ascertain whether MMP-1 has a role in the regulation of vascular reactivity, active enzyme was perfused into the lumen of intact omental arteries at varying concentrations and tested for vasoconstriction using a myograph system. We found that activated MMP-1 directly caused vessel contraction at 0.25 ng/ml (P Ͻ 0.05), 2.5 ng/ml (P Ͻ 0.001), and 25 ng/ml (P Ͻ 0.001) ( Figure 5).…”

“…[13][14][15][16] Beyond their matrix remodeling properties, MMPs are involved in short-term biological processes, including regulation of vascular reactivity and leukocyte activation. [17][18][19][20][21] Interestingly, these biological processes are altered in women with preeclampsia. 1,22,23 These observations led us to hypothesize that neutrophil infiltration could affect vascular expression of MMPs and other extracellular matrix proteins, resulting in vascular dysfunction in women with preeclampsia.…”

Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

“…Both are further processed into ET-1 by neutral endopeptidase (NEP). [17][18][19] Thus, a dual NEP/ECE inhibitor, for example the novel compound SOL1, reduces ET-1 production by inhibiting all three pathways. 20 Recently, Kalk et al 21 reported that the dual NEP/ECE inhibitor daglutril (SLV338, an analog of SOL1) reduced cardiomyocyte hypertrophy, interstitial fibrosis and perivascular fibrosis in the 2-kidney 1-clip model of hypertension.…”

Metalloproteinases in hypertension and cardiac disease: differential expression and mutual regulation

“…transforming growth factor-β (TGF-β)), cell surface receptors (e.g. β2-adrenergic receptor, vascular endothelial growth factor receptor-2 (VEGFR-2), insulin receptor) and extracellular matrix components [2][3][4][5][6][7][8][9][10]. We review here emerging evidence that MMPs and ADAMs are key mediators that might regulate one another (e.g.…”