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...
