Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty

Insulin-like growth factor (IGF)-I stimulates vascular smooth muscle cell ( VSMC) migration and proliferation, which are fundamental to neointimal hype rplasia in postangioplasty restenosis. IGF-I action is modulated by several high-affinity IGF binding proteins (IGFBPs). IGFBP-4 is the predominant IG FBP produced by VSMCs and is a potent inhibitor of IGF-I action. However, s pecific IGFBP-4 proteases can cleave IGFBP-4 and liberate active IGF-I. In this study, we document IGFBP-4 protease produced by human and porcine coro nary artery VSMCs in culture as pregnancy-associated plasma protein-A (PAPP -A). This was shown by a distinctive IGFBP-4 cleavage pattern, specific inh ibition of IGFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecognition of PAPP-A by monoclonal antibodies. Furthermore, we foun d a 2-fold increase in IGFBP-4 protease activity in injured porcine VSMC cu ltures in vitro (P<0.05). We also evaluated IGFBP-4 protease/PAPP-A express ion in vivo after coronary artery balloon injury, Twenty-five immature fema le pigs underwent coronary overstretch balloon injury, and vessels were exa mined at defined time points after the procedure. Abundant PAPP-A expressio n was observed in the cytoplasm of medial and neointimal cells 7, 14, and 2 8 days after angioplasty (P<0.01 vs control). The highest PAPP-A labeling i ndices were located in the neointima (36.1+/-2.1%) and the media (31.7+/-1. 2%) 28 days after injury. Western blot analysis confirmed increased PAPP-A in injured vessels. PAPP-A, a regulator of IGF-I bioavailability through pr oteolysis of IGFBP-4, is thus expressed by VSMCs in vitro and in restenotic lesions in vivo. These results suggest a possible role for PAPP-A in neoin timal hyperplasia.