Remodeling of the adventitia during coronary arteriogenesis

Abstract

We studied the role of the adventitia in adaptive arteriogenesis during the phase of active growth of coronary collateral vessels (CV) induced by chronic occlusion of the left circumflex coronary artery in canine hearts. We used electron microscopy and immunoconfocal (IF) labeling for bFGF, matrix metalloproteinase (MMP)-2, MMP-9, tissue-type plasminogen activator (tPA), its inhibitor (PAI-1), fibronectin (FN), and Ki-67. Proliferation of smooth muscle cells and adventitial fibroblasts was evident. Quantitative IF showed that adventitial MMP-2, MMP-9, and FN were 9.2-, 7.5-, and 8.6-fold, bFGF was 5.1-fold, and PAI-1 was 3.4-fold higher in CV than in normal vessels (NV). The number of fibroblasts was 5-fold elevated in CV, but the elastic fiber content was 25-fold greater in NV than in CV. Perivascular myocyte damage and induction of endothelial nitric oxide synthase in peri-CV capillaries indicate expansion of CV. It was concluded that adventitial activation is associated with the development of CV through cell proliferation, production of growth factors, and induction of extracellular proteolysis thereby contributing to remodeling during adaptive arteriogenesis. collateral vessel growth; metalloproteinases; extracellular proteolysis; dog CORONARY COLLATERAL VESSEL GROWTH in the dog heart, induced by chronic occlusion of a major coronary artery, results in a 20-50 times increase in diameter (21). The mechanism of collateral vessel growth is only partially understood. Many factors or events have been indicated to make contributions to this process, e.g., increased shear stress, early invasion of monocytes/ macrophages, reexpression of fetal proteins, extracellular proteolysis, migration of smooth muscle (SM) cells, and involvement of gap junction proteins (3,4,29). The notion that apoptosis of SM cells, fibroblasts, or myocytes creates space for the enlargement of collateral vessels has also been proposed (23). These studies addressed the crucial role of endothelium and of SM cells in the development of coronary collateral vessels.However, the importance of the tunica adventitia in vascular remodeling was largely neglected, although enlargement of collateral vessels without participation of the adventitia seems not conceivable. We hypothesize that the adventitia is activated and might be an important contributor to the development of coronary collaterals.The development of coronary collateral vessels has been classified into three phases: early growth (2-3 wk postsurgery), active growth (4-6 wk postsurgery), and maturation (8-12 wk postsurgery) (4). An early study showed that an acute inflammatory reaction was present in the adventitia of collateral vessels in the phase of early growth (2). However, in the phases of active growth and maturation, inflammatory cells have not been observed in the adventitia, and fibroblasts are the predominant cells residing in the adventitia. Fibroblasts have been demonstrated to be active participants in vascular remodeling (20,25,26). Here, we studied the question whether typica...

Myocardial Salvage Through Coronary Collateral Growth by Granulocyte Colony-Stimulating Factor in Chronic Coronary Artery Disease

“…Aside from G-CSF, there have been well-investigated substances with arteriogenic efficacy such as monocyte chemoattractant protein-1 23 ; another colony-stimulating factor, granulocytemonocyte CSF (GM-CSF); 24 transforming growth factor ␤1 25 ; fibroblast growth factors 26 ; tumor necrosis factor ␣ 27 ; and matrix metalloproteinases. 28 Among these, only colonystimulating factors have been investigated for clinical use in coronary or peripheral artery disease, whereby GM-CSF has been shown to be effective in the former but not the latter condition. 20,21,29 However, inherent to all the arteriogenic substances is a certain proatherogenic risk because of the shared pathogenic monocyte involvement and inflammation in both processes.…”

Factors Regulating Arteriogenesis

“…In addition to actin and myosin, desmin and calponin are downregulated and fibronectin is upregulated. 82 In general, protein synthesis in SMCs switches to an embryonic pattern.…”

Smoking, Metalloproteinases, and Vascular Disease

“…41,44,45 Furthermore, matrix metalloproteinase expression is associated with remodeling of the vascular adventitia. 42,46 Characteristics of unstable plaques susceptible to rupture include a large lipid core, a thin fibrous cap, 47 and intraplaque hemorrhage. 48 Matrix metalloproteinases are expressed within atherosclerotic plaques, 49 particularly at the shoulder regions, 50 where increased stresses and matrix degradation may combine to rupture the fibrous cap.…”