Agonist-Induced Activation of Matrix Metalloproteinase-7 Promotes Vasoconstriction Through the Epidermal Growth Factor–Receptor Pathway

Abstract

Abstract-Matrix metalloproteinase (MMP)-dependent shedding of heparin-binding epidermal growth factor (HB-EGF) and subsequent activation of the EGF receptor (EGFR) in the cardiovasculature is emerging as a unique mechanism signaling growth effects of diverse G protein-coupled receptors (GPCRs). Among these GPCRs are adrenoceptors and angiotensin receptors that contribute to the pathogenesis of hypertension through their vasoconstrictive and growth effects. Focusing on ␣ 1b -adrenoceptors, we suggest here that MMP-dependent activation of the EGFR promotes vasoconstriction as well as growth. We identified MMP-7 as a major HB-EGF sheddase in rat mesenteric arteries and ␣ 1b -adrenoceptors, angiotensin receptors, and hypertension-stimulated MMP-7 activity. Adrenoceptors stimulated EGFR autophosphorylation in arteries, and this transactivation was opposed by the MMP-7 inhibitor GM6001 as well as MMP-7-specific antibodies. In isolated microperfused arteries, blockade of EGFR transactivation with inhibitors of the EGFR (AG1478 and PD153035), HB-EGF (CRM197 and neutralizing antibodies), or MMPs (doxycycline) inhibited adrenergic vasoconstriction. In spontaneously hypertensive rats but not in normotensive rats, the inhibition of MMPs with doxycycline (19.2 mg/d from week 7 until week 12) reduced systolic blood pressure and attenuated HB-EGF shedding in the mesenteric arteries. These findings suggest a previously unknown mechanism of vasoregulation whereby agonists of certain GPCRs (such as adrenoceptors and angiotensin receptors) activate MMPs (such as MMP-7) that shed EGFR ligands (such as HB-EGF), which then activate the EGFR, thereby promoting vasoconstriction as well as growth. Because this mechanism is triggered by agonists typically overexpressed in hypertension, its blockade may have therapeutic potential for simultaneously inhibiting pathological vasoconstriction and growth in hypertensive disorders. Key Words: matrix metalloproteinase Ⅲ heparin-binding epidermal growth factor Ⅲ epidermal growth factor receptor Ⅲ vasoconstriction Ⅲ hypertension T here is increasing evidence implicating matrix metalloproteinases (MMPs) and metalloproteinase disintegrins (ADAMs) in shedding of growth factors (eg, heparin-binding epidermal growth factor [HB-EGF]) and thereby transactivation of cognate growth factor receptors (eg, EGF receptor) in the development of hypertrophy associated with hypertension. [1][2][3][4][5][6][7] In the heart, one mechanism of hypertrophy is transactivation of the EGF receptor by G protein-coupled receptors (GPCRs), such as adrenoceptors, angiotensin, and endothelin receptors, whose agonists (catecholamines, angiotensin II, and endothelins) are typically overexpressed as well as being historically implicated in the initiation, progression, and development of hypertensive disorders. 4,8 -12 These GPCRs transactivate the EGF receptor (EGFR) in cardiomyocytes via a shared pathway, whereby ADAM 12 sheds membraneanchored HB-EGF, which then binds to the EGFR either directly or via an interaction with the...

Functions of epidermal growth factor receptor in cisplatin response of thyroid cells

“…ligands cleaved by MMPs, is also described [13,14]. Finally, the cisplatin-induced cytotoxicity seems to be closely associated with the increased production of reactive oxygen species (ROS) [15] and ROS contribute to cell death partly through effects on various cellular signalling pathways, including the mitogen-activated protein kinase (MAPK) pathway [16].…”

“…An alternative mechanism to p38/MAPK, for EGFR transactivation, is the autocrine/paracrine release of soluble EGF ligands [56]. HB-EGF, epiregulin, and TGF-α can activate EGFR; these ligands are synthesized as transmembrane proteins (proforms) and cleaved by metalloproteases to yield soluble forms, thereby binding and leading to EGFR activation [13,14]. Indeed, we detected a baseline MMP-2 activity in conditioned media from PC Cl3 cells, and such activity, and MMP-2 protein expression, increased in a time-dependent manner after cisplatin treatment (Fig.…”

Metalloproteinases: key and common mediators of multiple GPCRs and candidate therapeutic targets in models of hypertensive cardiac disease

“…We have identified MMP-2, MMP-7, ADAM-12 and ADAM-17/TACE as mediators of angiotensin II-induced hypertensive cardiac disease. We have also found that gene expression of these metalloproteinases changes throughout disease development [16,36,[40][41][42]. Moreover, some MMPs and ADAMs (such as MMP-7 and ADAM-17) appear to regulate others (such as MMP-2 and ADAM-12).…”

“…Another non-ECM acute action of MMPs and ADAMs is shedding of membrane-anchored ligands of receptors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) to transactivate intracellular signaling of growth via the MAPK cascade. Thus, metalloproteinases modulate MAPK signaling to help maintain agonist-induced vascular tone and signaling of hypertrophic growth [36].…”

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.…”