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Circulation Research. 2007;100:749-750
doi: 10.1161/01.RES.0000263398.47653.ef
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(Circulation Research. 2007;100:749.)
© 2007 American Heart Association, Inc.

Editorials

The Matrix Revolutions

Matrix Metalloproteinase, Vasculogenesis, and Ischemic Tissue Repair

Marie-Ange Renault, Douglas W. Losordo

From the Feinberg Cardiovascular Research Institute and Program in Cardiovascular Regenerative Medicine, Division of Cardiovascular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital (M.-A.R., D.W.L.), Chicago, Ill.

Correspondence to Douglas W. Losordo, MD; Feinberg Cardiovascular Research Institute and Northwestern Memorial Hospital, Tarry 12-703, 303 E. Chicago Avenue, Chicago, IL 60611. E-mail d-losordo{at}northwestern.edu



See related article, pages 904–913


Key Words: angiogenesis • vasculogenesis • matrix metalloproteinases

The matrix metalloproteinase (MMP) family of Zinc dependent extracellular proteinases regulates development and physiologic events, including branching morphogenesis, angiogenesis, wound healing and extracellular matrix degradation. They are synthesized as secreted or transmembrane proenzymes and processed to an active form by the removal of an amino-terminal propeptide. MMP-2/Gelatinase A, as well as MMP-9/gelatinase B, which belong to the gelatinase subclass of the MMP family, have been shown to play a central role in initiating angiogenesis1,2 and to be upregulated after hindlimb ischemia.3 They are involved in degrading extracellular and basement membrane structures, allowing endothelial migration to occur. In addition, MMPs promote the release of extracellular matrix-bound cytokines, such as vascular endothelial growth factor (VEGF), which can regulate angiogenesis.4

Both MMP-2 and MMP-9 expression have been shown to be upregulated in bone marrow and peripheral blood derived CD34 positive cells treated by stromal cell derived factor-1.5 Only MMP-9 had been shown to be involved in vasculogenesis and more particularly endothelial progenitor cell (EPC) mobilization. First, MMP-9 has been shown to be upregulated in the bone marrow and necessary for VEGF-, placental growth factor- and by stromal cell derived factor-1–induced EPC recruitment.6,7,8 Increased MMP-9 activity in the bone marrow has been shown to induce the release of soluble kit ligand (skitL) promoting the proliferation and motility of hematopoietic stem cell and EPCs within the bone marrow.6 The role of MMP-9 in EPC mobilization has been confirmed in several studies. For example, it has been shown to be involved in estradiol (E2)-induced neovascularization after myocardial infarction. Indeed, MMP-9 activity is increased in the spleen of E2-treated mice and is essential for EPC mobilization induced by estradiol after myocardial infarction in the mice.9 Also, angiotensin converting enzyme, or HMG CoA reductase inhibition have been shown to promote EPC recruitment to infarcting myocardium and increase MMP-9 activity within the bone marrow.10 Reduced MMP-9 expression has also been associated with impaired circulating progenitor cell migration and invasion in the case of hyperglycemia.11

In this issue, Cheng et al12 investigate the role of MMP-2 in ischemia-induced neovascularization in the limb muscle and disclose several potential mechanisms by which MMP-2 deficiency leads to impaired neovascularization. First the authors confirm that MMP-2 expression is upregulated in ECs (endothelial cells) after VEGF or bFGF treatment,13 and show that VEGF-dependent angiogenesis in aortic-ring culture as well as VEGF-directed EC invasion are impaired in the absence of MMP-2. After they confirmed the role of MMP-2 in angiogenesis, they report here for the first time that MMP-2 is also involved in post natal vasculogenesis and more precisely in EPC mobilization. The seminal observation is that the number of CD31+, c-Kit+ cells circulating in the peripheral blood 10 days after ligation of the femoral artery is reduced in MMP-2 deficient mice. The importance of this finding, and the deficient ischemic response, is supported by the fact that bone marrow transplant from wild type mice rescues neovasculogenesis in MMP-2–/– mice.

A third mechanisms by which MMP-2 participates in ischemia-induced neovascularization is also described in this article: MMP-2 promotes the recruitment of VEGF expressing macrophages and leukocytes into ischemic tissues. This MMP-2 deficiency also leads to reduced VEGF in the ischemic tissue and peripheral blood. MMP-9 has also been shown to promote mast cell recruitment and VEGF release within ischemic tissue.14

Both MMP-2 and MMP-9 have thus been implicated in EPC mobilization. A mechanism by which MMP-9 promotes EPC mobilization, involving c-KitL, has been described. The exact mechanism underlying the effect of MMP-2 on EPC remains to be described; nevertheless, like MMP-9, MMP-2 is shown to promote EPC proliferation. Because MMP-9 is overexpressed in MMP-2 deficient mice15 as well as its activity in the ischemic tissue (results shown in this issue), compensatory mechanisms might occur. Nevertheless both MMP-9 and MMP-2 appear necessary for normal EPC mobilization induced by ischemia. If MMP-9 and MMP-2 belong to the same group of proteinase and are both involved in angiogenesis and vasculogenesis, the regulation of their expression is different: MMP-9 is expressed at higher levels by early EPCs (CD14+), whereas MMP-2 has been shown to be more expressed by outgrowth endothelial cells (OECs) (CD14–).16 MMP-2 expression is increased after VEGF treatment in both OECs and EPCs even if it stays higher in OECs whereas MMP-9 expression is only upregulated by VEGF in EPCs.16 Also the localization of MMP-2 on the cell membrane is associated with the integrin {alpha}vß317 whereas MMP-9 is associated with CD44.18

Outside of MMP-2 and MMP-9, cathepsin L, a cystein protease, has been shown to be highly expressed by EPC and promotes matrix degradation and invasion of EPCs,19 EPC recruitment is impaired in Cathepsin L deficient mice, but it has been shown not to be involved in EPC mobilization but rather in EPC homing. In 1995, Granzyme B, an hematopoietic serine protease, have been involved in G-CSF and chemotherapy induced CD34+ cells mobilization.20

Thus the work of Cheng et al provides another pathway by which ischemia modulates the kinetics of EPCs, providing certain insights regarding the regulation of postnatal vasculogenesis as well as raising additional questions regarding the precise molecular pathways involved. These findings have important implications, not only in our understanding of ischemic tissue repair, but may also evolve into important therapeutic targets in other realms such as cancer, fertility, and bone and joint disease.


*    Acknowledgments
 
We thank M. Neely for secretarial assistance.

Sources of Funding

This study was supported in part by NIH grants (HL53354, HL57516, HL77428, HL63414, HL80137, PO1HL-66957).

Disclosures

None.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
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