Exogenous application of transforming growth factor beta 1 stimulates arteriogenesis in the peripheral circulation

Increased expression of transforming growth factor beta1 (TGF-beta1) during collateral artery growth, as well as its numerous effects on monocytes/macrophages and the smooth muscle cell cycle and differentiation, suggest a modulating role for this growth factor during arteriogenesis. We studied the effects of exogenously applied TGF-beta1 on arteriogenesis as well as its interactions with monocytes, endothelial cells, and smooth muscle cells. In a New Zealand White (NZW) rabbit model of femoral artery ligation, increased expression of active TGF-beta1 was found around proliferating arteries in NZW rabbits. The exogenous application of TGF-beta1 led to an increase in both the number of visible collateral arteries as well as the conductance of the collateral circulation (4.0 +/- 0.5 ml/min/100 mmHg vs. 28.9 +/- 3.7 ml/min/100 mmHg, P<0.05). Fluorescence activated cell sorting analysis showed an increase in the expression of the MAC-1 receptor in both rabbit and human monocytes after treatment with TGF-beta1 (control: 91.2 +/- 4.2/482 +/- 21.7; TGF-beta1 200 ng/ml 193.9 +/- 6.7/ 675.5 +/- 25.7, P<0.05 for all differences). TGF-beta1 treated monocytes showed an increased endothelial adhesion and transmigration in transendothelial migration assays (5.75 +/- 0.63 x 10(5) vs. 10.11 +/- 0.04 x 10(5), P<0.05). TGF-beta1 had no direct pro-angiogenic effect on human umbilical vein endothelial cells in a spheroid model of angiogenesis and inhibited the angiogenic effects of vascular endothelial growth factor.