Abnormal growth of vascular smooth muscle cells is a characteristic of many cardiovascular diseases. This abnormal growth occurs during the development of an atherosclerotic lesion and during the development of a restenotic lesion following angioplasty. We hypothesize that in the normal adult vessel, the vascular smooth muscle cells are exposed to a delicate balance of-growth stimulators and inhibitors, resulting in a stable population of quiescent vascular smooth muscle cells within the media. However, following injury, the balance of growth stimulators and inhibitors are shifted to favor growth and migration. In the past, our research has focused on many of the factors which promote growth such as Ang Il or growth factors. Recently, we have begun an examination of growth inhibitors, concentrating on the effects of the Atrial Natriuretic Peptide (ANP) family. This family is composed of three distinct members, ANP, BNP and CNP. ANP and BNP are the major circulating forms of the family that exert their biological effects via the ANPA receptor. On the other hand, CNP does not appear to be present in high concentrations in the plasma and exerts it biological effects via a distinct receptor, ANPB. All three peptides also bind to and may exert actions through the ANPc receptor isoform. We and others have shown that ANP will inhibit the growth of vascular smooth muscle cells. It is controversial as to whether these effects are mediated via the ANPA or the ANPc receptors. -However, our preliminary results suggest that after vascular injury, the expression of both the ANPA and the ANPc receptor isoform in the vessel wall decreases while the third form of the receptor, ANPB, is induced. This form of the receptor does not recognize ANP, the major circulating natriuretic peptide but is specific for CNP which is not present in normal adult plasma. Based on this evidence, we hypothesize that the switch in ANP receptor expression plays a contributing role in the development of the neointimal lesion since the vessel wall will be less responsive to a circulating growth inhibitor. We propose to examine, in more detail this switch in receptor expression and the consequences of this shift in terms of vascular smooth muscle cell growth. Using both in vivo and cell culture models, we will examine the receptor expression by a combination of molecular and biochemical techniques. We will examine the effects of the natriuretic peptides on the growth of vascular smooth muscle cells and will use gene transfer techniques to address the controversy concerning the identity of the isoform which mediates the antiproliferative actions. The results of this study should provide new insight into the identity of the factors which control the growth of vascular smooth muscle cells in vivo. We anticipate that the identification of factors which will inhibit growth following injury may suggest possible treatment strategies to block the initiation or progression of atherosclerotic occlusive disease.
Showing the most recent 10 out of 50 publications
