Remodeling of the vascular tunica media is essential for development of collateral vessels in the canine heart

Abstract

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.

Induction of Cerebral Arteriogenesis Leads to Early-Phase Expression of Protease Inhibitors in Growing Collaterals of the Brain

“…Earlier, TIMP-1 has been reported to be transcriptionally upregulated in a model for coronary arteriogenesis in the dog heart (Cai et al, 2004). In our study, mRNA ISH analysis showed TIMP-1-positive mRNA staining in the intima, media, and adventitia of the PCA during arteriogenesis 24 h after 3-VO ( Figure 3A).…”

Arteriogenesis versus angiogenesis: similarities and differences

“…It comprises the induction of vascular wall cell proliferation and migration and includes wall remodelling processes. In consequence, the structural enlargement of collateral arterioles to arteries proceeds as an active growth rather than by a passive dilatation caused by the altered blood pressure [7][8][9] The initial trigger defines the mechanism Angiogenesis and arteriogenesis are initiated by distinct initial triggers. Especially during tissue expansion such as in growing tumors but also in ischemic tissues, adaptive growth of capillaries is initiated as a reaction to hypoxia [10][11][12].…”

The Formation of Aberrant Collateral Vessels during Coronary Arteriogenesis in Dog Heart

“…In the phase of active growth the cells of both the tunica media and adventitia are activated, indicated by reexpression of fetal proteins in smooth muscle cells (SMCs), active extracellular proteolysis, proliferation and migration of SMCs and fibroblasts, and neointima formation [Wolf et al, 1998;Cai et al, 2000Cai et al, , 2001Cai et al, , 2003]. In the maturation phase the collateral vessels stop growing and the SMCs of the neointima are present in the contractile phenotype with high levels of both the cytoskeletal and contractile proteins, for example desmin, α-SM actin and calponin [Cai et al, 2000[Cai et al, , 2004b. The outcome of vascular remodeling leads to larger arterial vessels that conduct blood to the ischemic regions.…”