Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (arteriogenesis)

Previous studies in the canine heart had shown that the growth of collatera l arteries occurs via proliferative enlargement of pre-existing arteriolar connections (arteriogenesis). In the present study, we investigated the ult rastructure and molecular histology of growing and remodeling collateral ar teries that develop after femoral artery occlusion in rabbits as a function of time from 2 h to 240 days after occlusion. Pre-existent arteriolar coll aterals had a diameter of about 50 mu m. They consisted of one to two layer s of smooth muscle cells (SMCs) and were morphologically indistinguishable from normal arterioles. The stages of arteriogenesis consisted of arteriola r thinning, followed by transformation of SMCs from the contractile- into t he proliferative- and synthetic phenotype. Endothelial cells (ECs) and SMCs proliferated, and SMCs migrated and formed a neo-intima. Intercellular adh esion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) showed early upregulation in ECs, which was accompanied by accumulation of blood- derived macrophages. Mitosis of ECs and SMCs started about 24 h after occlu sion, whereas adhesion molecule expression and monocyte adhesion occurred a s early as 12 h after occlusion, suggesting a role of monocytes in vascular cell proliferation. Treatment of rabbits with the pro-inflammatory cytokin e MCP-I increased monocyte adhesion and accelerated vascular remodeling. In vitro shear-stress experiments in cultured ECs revealed an increased phosp horylation of the focal contacts after 30 min and induction of ICAM-1 and V CAM-1 expression between 2 h and 6 h after shear onset, suggesting that she ar stress may be the initiating event. We conclude that the process of arte riogenesis, which leads to the positive remodeling of an arteriole into an artery up to 12 times its original size, can be modified by modulators of i nflammation.