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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...

Previous studies have shown that neointima formation and adventitial remodeling play an important role in the enlargement of collateral vessels (CVs) during coronary arteriogenesis in the dog heart. In this study, we investigated the importance of remodeling of the tunica media in the same model. Basal membrane (BM), contractile and cytoskeletal components of smooth muscle cells (SMCs) were studied in growth of coronary CVs induced by chronic occlusion of the left circumflex (LCX) coronary artery by routine histology, electron microscopy (EM), and immunoconfocal microscopy using antibodies against alpha-smooth actin (alpha-SM actin), calponin, desmin, and laminin. In addition, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor-1 of matrix metalloproteinase (TIMP-1) were investigated. The data showed that (1) in normal small arteries (NVs) laminin formed a network in which SMCs were encaged; alpha-SM actin, calponin and desmin were evenly expressed in SMCs; (2) in early (2 weeks) growing CVs the laminin network was disrupted, desmin was significantly reduced in SMCs, but alpha-SM actin and calponin still highly expressed; (3) in actively (6 weeks) growing CVs laminin was still weak in the tunica media (TM), but without network-like structure. Desmin was further reduced in SMCs of TM, whereas alpha-SM actin and calponin showed little changes, although they were significantly decreased in intimal SMCs; (4) in mature CVs, the network-like structure was re-formed, and alpha-SM actin, calponin, and desmin were all similar to that in normal vessels; (5) histology for BM confirmed laminin staining; (6) EM revealed that in NVs the SMCs contained abundant contractile filaments and were surrounded by a layer of BM whereas in growing CVs, BM structure was not observed, but the SMCs in the media still contained many myofilaments; (7) MMP-2 was highly expressed in the media of early growing vessels, but decreased in TM of actively growing vessels where TIMP-1 expression was high. In conclusion, our data revealed features of TM of growing CVs. Disruption and degradation of BM facilitate SMC proliferation, and together with reduction of desmin and fragmentation of the internal elastic lamina enable the vascular wall to expand and enlarge when blood pressure and shear stress increase. MMP2 may be an important player in regulating SMC phenotype, proliferation, migration and maintaining integrity of the vascular wall through governing proteolysis during arteriogenesis.