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Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth

Li Hao1, Min Du, Ana Lopez-Campistrous

  • 1Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.

Circulation Research
|December 6, 2003
PubMed

Insights

Matrix metalloproteinases (MMPs) shed heparin-binding epidermal growth factor (HB-EGF), activating the EGF receptor (EGFR) to promote vasoconstriction and growth. This pathway, linked to hypertension, offers a potential therapeutic target.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Signaling
  • Hypertension Pathogenesis

Background:

  • G protein-coupled receptors (GPCRs), like adrenoceptors and angiotensin receptors, contribute to hypertension via vasoconstriction and growth.
  • GPCR signaling can involve matrix metalloproteinase (MMP)-dependent shedding of heparin-binding epidermal growth factor (HB-EGF), leading to EGF receptor (EGFR) activation.

Purpose of the Study:

  • To investigate the role of MMP-dependent HB-EGF shedding and EGFR activation in alpha(1b)-adrenoceptor-mediated vasoconstriction and growth.
  • To determine if this mechanism is relevant in the context of hypertension.

Main Methods:

  • Utilized rat mesenteric arteries and spontaneously hypertensive rats.
  • Employed MMP-7 inhibitors, MMP-7 specific antibodies, EGFR inhibitors, and HB-EGF blocking agents.
  • Administered doxycycline to inhibit MMPs in vivo and measured systolic blood pressure and HB-EGF shedding.

Main Results:

  • Identified MMP-7 as a key HB-EGF sheddase in rat mesenteric arteries.
  • Demonstrated that alpha(1b)-adrenoceptor stimulation leads to EGFR transactivation, which was blocked by MMP inhibitors and antibodies.
  • In spontaneously hypertensive rats, MMP inhibition with doxycycline reduced blood pressure and HB-EGF shedding.

Conclusions:

  • A novel vasoregulation mechanism involves GPCR agonists activating MMPs to shed EGFR ligands, promoting vasoconstriction and growth.
  • This MMP-dependent EGFR transactivation pathway is implicated in hypertension.
  • Blocking this pathway may offer a therapeutic strategy for hypertension by inhibiting both vasoconstriction and pathological growth.

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