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Matrix metalloproteinase-9 is essential for ischemia-induced neovascularization by modulating bone marrow-derived

Po-Hsun Huang1, Yung-Hsiang Chen, Chao-Hung Wang

  • 1Division of Cardiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan.

Arteriosclerosis, Thrombosis, and Vascular Biology
|May 23, 2009
PubMed
Abstract

Insights

Matrix metalloproteinase-9 (MMP-9) deficiency impairs blood flow recovery after ischemia by hindering endothelial progenitor cell (EPC) function. This study reveals MMP-9 is crucial for EPC mobilization and vasculogenesis, essential for neovascularization.

Area of Science:

  • Cardiovascular Biology
  • Regenerative Medicine
  • Molecular Biology

Background:

  • Neovascularization is critical for tissue repair following ischemic events.
  • Matrix metalloproteinases (MMPs) and endothelial progenitor cells (EPCs) play key roles in blood vessel formation.
  • MMP-9's specific role in EPC function and neovascularization remains to be fully elucidated.

Purpose of the Study:

  • To investigate the impact of MMP-9 deficiency on EPC function and neovascularization in a mouse model of hindlimb ischemia.
  • To determine the mechanisms by which MMP-9 influences EPC mobilization and vasculogenesis.

Main Methods:

  • Hindlimb ischemia surgery was performed on MMP-9 knockout (MMP-9(-/-)) and wild-type (MMP-9(+/+)) mice.
  • Blood flow recovery was assessed using laser Doppler imaging.
  • Flow cytometry analyzed EPC-like cell populations (Sca-1(+)/Flk-1(+)) and C-kit positive bone marrow cells.
  • Plasma and bone marrow levels of soluble Kit-ligand (sKitL) were measured.
  • In vitro studies assessed EPC colony formation, migration, and tube formation with and without MMP-9 inhibition.
  • Bone marrow transplantation was performed to evaluate functional restoration.

Main Results:

  • MMP-9(-/-) mice exhibited significantly impaired blood flow recovery compared to wild-type mice.
  • Ischemia failed to increase EPC-like cell numbers and sKitL levels in MMP-9(-/-) mice.
  • MMP-9 deficiency attenuated the adhesion and migration of C-kit positive bone marrow cells.
  • In vitro, MMP-9 inhibition suppressed EPC colony formation, migration, and tube formation.
  • Transplantation of wild-type bone marrow cells restored collateral flow in MMP-9(-/-) mice.

Conclusions:

  • MMP-9 deficiency impairs ischemia-induced neovascularization.
  • These effects are mediated by reduced stem cell-active cytokine release, leading to impaired EPC mobilization, migration, and vasculogenesis.
  • MMP-9 is essential for effective EPC function and neovascularization in response to ischemic injury.

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