Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF.

Approximately 30 to 40 percent of atherosclerotic coronary arteries treated by angioplasty or by bypass surgery occlude as a result of restenosis. This restenosis is due principally to the accumulation of neointimal smooth muscle cells, which is also a prominent feature of the advanced lesions of atherosclerosis. The factors responsible for the accumulation of intimal smooth muscle cells have not been identified. Platelet-derived growth factor (PDGF) is a potent smooth muscle chemoattractant and mitogen. It is present in platelets and can be formed by endothelium, smooth muscle, and monocyte-derived macrophages. The development of an intimal lesion in the carotid artery of athymic nude rats induced by intraarterial balloon catheter deendothelialization was inhibited by a polyclonal antibody to PDGF. These data demonstrate that endogenous PDGF is involved in the accumulation of neointimal smooth muscle cells associated with balloon injury and may be involved in restenosis after angioplasty, and perhaps in atherogenesis as well.

Recombinant insulin-like growth factor-1 modulates aggregation in human platelets via extracellular calcium.

Insulin like growth factor-1 (IGF-1) potentiated aggregation of human platelets induced by thrombin-, collagen- and ADP in a dose-dependent manner over the range 30-300 nM. IGF-1 (100 nM) reduced EC50 values for thrombin, collagen and ADP-induced aggregation by 19.6%, 53.6% and 22.8% respectively. Potentiation by IGF-1 was dependent on the presence of extracellular Ca2+ and was inhibited by verapamil or nifedipine. Further, IGF-1 enhanced the elevation in free intraplatelet Ca2+ induced by the platelet agonists collagen and thrombin.

The insulin-like growth factors: their putative role in atherogenesis.

Smooth muscle cell proliferation and leukocyte infiltration are characteristic features of all lesions of atherosclerosis. Although platelet derived growth factor (PDGF) is one of the major smooth muscle mitogens, other important mitogenic factors are found in plasma and in platelets. The insulin-like growth factors (IGF-I and IGF-II) are present in plasma complexed to one of a number of IGF-binding proteins (IGF-BP). They are also found at high concentrations within the alpha-granules of platelets. The IGFs are secreted by a number of cell types in-vitro and in-vivo, including smooth muscle cells and macrophages. The cellular effects of the IGFs are mediated by membrane bound high affinity receptors. IGF receptors are of two distinct types and are expressed by a wide variety of cells. The IGFs are potent smooth muscle cell mitogens and it is therefore possible that these polypeptides contribute to the formation of the atherosclerotic lesion by paracrine, autocrine or endocrine mechanisms.

Biochemical characterization of two angiotensin II receptor subtypes in the rat.

Two angiotensin II receptor subtypes, A and B, have been described by means of specific and selective ligands (Biochem Biophys Res Commun 1989; 163:284-91). The present report describes the binding characteristics and the distribution of these subtypes in various rat tissues. Adrenal and uterus expressed both subtypes but in different proportions. Subtype B predominated in the adrenal glomerulosa (60%), whereas there was a greater proportion of subtype A in the medulla (70%). In uterus, subtype B was preferentially expressed (70%), and there was no difference in receptor distribution between muscle layers and serosa. Liver, kidney, and cultured aortic smooth muscle cells expressed only subtype B. In all of the tissues tested, the Ki values of various competing ligands were similar for each subtype expressed. It is proposed that subtype B is the vascular receptor. The function of subtype A, however, is still to be determined.