Excessive accumulation of smooth-muscle cells (SMCs) has a key role in the pathogenesis of vascular diseases. It has been assumed that SMCs derived from the outer medial layer migrate, proliferate and synthesize extracellular matrix components on the luminal side of the vessel. Although much effort has been devoted to targeting migration and proliferation of medial SMCs, there is no effective therapy that prevents occlusive vascular remodeling. We show here that in models of post-angioplasty restenosis, graft vasculopathy and hyperlipidemia-induced atherosclerosis, bone-marrow cells give rise to most of the SMCs that contribute to arterial remodeling. Notably, purified hematopoietic stem cells differentiate into SMCs in vitro and in vivo. Our findings indicate that somatic stem cells contribute to pathological remodeling of remote organs, and may provide the basis for the development of new therapeutic strategies for vascular diseases through targeting mobilization, homing, differentiation and proliferation of bone marrow-derived vascular progenitor cells.

Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis

Hematopoietic Stem Cells Differentiate into Vascular Cells That Participate in the Pathogenesis of Atherosclerosis

Intimal thickening, the accumulation of cells and extracellular matrix within the inner vessel wall, is a physiological response to mechanical injury, increased wall stress, or chemical insult (e.g., atherosclerosis). If excessive, it can lead to the obstruction of blood flow and tissue ischemia. Together with expansive or constrictive remodeling, the extent of intimal expansion determines final lumen size and vessel wall thickness. Plaque rupture represents a failure of intimal remodeling, where the fibrous cap overlying an atheromatous core of lipid undergoes catastrophic mechanical breakdown. Plaque rupture promotes coronary thrombosis and myocardial infarction, the most prevalent cause of premature death in advanced societies. The matrix metalloproteinases (MMPs) can act together to degrade the major components of the vascular extracellular matrix. All cells present in the normal and diseased blood vessel wall upregulate and activate MMPs in a multistep fashion driven in part by soluble cytokines and cell-cell interactions. Activation of MMP proforms requires other MMPs or other classes of protease. MMP activation contributes to intimal growth and vessel wall remodeling in response to injury, most notably by promoting migration of vascular smooth muscle cells. A broader spectrum and/or higher level of MMP activation, especially associated with inflammation, could contribute to pathological matrix destruction and plaque rupture. Inhibiting the activity of specific MMPs or preventing their upregulation could ameliorate intimal thickening and prevent myocardial infarction.

Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture

Intimal thickening occurs in blood vessels in response to injury or atherosclerosis. The balance of migration and proliferation of vascular smooth muscle cells (VSMC) over death by apoptosis has an important impact on the final size of intimal thickening and may also affect atherosclerotic plaque stability. All aspects of VSMC behaviour are under coordinated control by growth factors, cell-matrix and cell-cell interactions. We review the evidence that matrix-degrading metalloproteinases (MMPs) regulate migration, proliferation and survival of VSMC. Moreover, we discuss critically the underlying mechanisms, which include changing growth factor availability and remodelling cell-matrix and cell-cell contacts. We conclude that MMPs influence VSMC behaviour by cleaving both matrix and non-matrix substrates.

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Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates

Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions.

Background—Intimal hyperplasia is the principal mechanism of in-stent restenosis. Matrix metalloproteinases (MMPs) play a key role in intimal growth after balloon angioplasty (BA). Little is known, however, about MMP expression after stent implantation (ST). We investigated whether MMP9 and MMP2 are differentially expressed after ST and BA. Methods and Results—Hypercholesterolemic rabbits underwent ST and BA in the right and left iliac arteries, respectively. The expression of MMPs and their inhibitors (TIMPs) was studied at various time points in the injured arteries by use of zymography, reverse transcription–polymerase chain reaction, and immunohistochemistry. MMP2, but not MMP9, was constitutively expressed in uninjured arteries. MMP9 expression was rapidly induced after injury, whereas the increase in MMP2 expression was delayed. At all time points, pro-MMP9 activity and MMP9 mRNA levels were ≥2-fold (ANOVA, P=0.002) and ≥3-fold (P<0.0001) higher after ST than after BA, respectively. Active MMP9 was ...

Differential Expression of Matrix Metalloproteinases After Stent Implantation and Balloon Angioplasty in the Hypercholesterolemic Rabbit

Patterns of use and potential impact of early β-blocker therapy in non–ST-elevation myocardial infarction with and without heart failure: The Global Registry of Acute Coronary Events

La pose de stents est devenue la principale technique d’angioplastie coronaire percutanee en France, comme dans les autres pays occidentaux. La principale limite de cette technique est la survenue de restenoses au site d’implantation du stent. Les techniques medicamenteuses de prevention, inefficaces dans l’ensemble, souffrent autant d’une meconnaissance de la physiopathologie des restenoses intrastent que d’une inadequation entre des traitements systemiques et un phenomene biologique eminemment focal. Des traitement locaux prenant en compte ces donnees physiopathologiques sont donc en cours d’evaluation chez l’homme. Les premiers resultats cliniques des stents impregnes actifs, qui permettent de delivrer localement de fortes concentrations de substances antiproliferantes (sirolimus, paclitaxel…), sont tres prometteurs et suggerent que ces nouveaux stents devraient probablement revolutionner la pratique de la cardiologie interventionnelle. Quant a la therapie genique, son application au probleme des restenoses necessite une simplification et une amelioration de l’efficacite des techniques de transfert genique.

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Aliocha Scheuble

Papers

Differential Expression of Matrix Metalloproteinases After Stent Implantation and Balloon Angioplasty in the Hypercholesterolemic Rabbit

Patterns of use and potential impact of early β-blocker therapy in non–ST-elevation myocardial infarction with and without heart failure: The Global Registry of Acute Coronary Events

Prévention des resténoses intrastent: vers un traitement in situ