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Endothelin (ET) and bone morphogenic proteins (BMP) have been implicated in the development of micro- and macrovascular complications of type 2 diabetes mellitus due to atherosclerosis. This study investigated vascular BMP-expression during early development of experimental autoimmune diabetes mellitus and whether ET(A) receptors are involved in its regulation, using the selective ET(A) receptor antagonist BSF461314. Specificity of BSF461314 was confirmed through ET-mediated p44/42 mitogen-activated protein kinase (ERK1/2) phosphorylation experiments. For animal studies, non-obese diabetic (NOD) and control mice at 16 weeks of age were treated with BSF461314 for 6 weeks. Plasma glucose levels were measured before and after treatment and vascular gene expression of BMP-2, BMP-7, and BMP-type II receptor was determined in the aorta by quantitative real-time polymerase chain reaction analysis. At the beginning of the study in all animals, plasma glucose levels were within the normal range. After 6 weeks gene expression of vascular BMP-2, BMP-7 and BMP-type II receptor was almost doubled in NOD mice compared with non-diabetic controls (p < 0.05). Concomitant treatment with BSF461314 significantly reduced expression of all BMPs and lowered plasma glucose levels in NOD mice close to controls (all p < 0.05 versus untreated). In conclusion, vascular BMP-2, BMP-7, and BMP-type II receptor expression is upregulated in early stages of autoimmune diabetes mellitus. The data further indicate that ET(A) receptors inhibit diabetes-associated activation of vascular BMPs and regulate plasma glucose levels suggesting that ET(A) receptors might provide a new therapeutic target to interfere with the early development of atherosclerosis in patients with type 1 diabetes mellitus.

Bone morphogenetic proteins (BMPs) stimulate ectopic bone formation in skeletal muscle. Here we show that human vascular smooth muscle cells (VSMC) abundantly express mRNA encoding for BMP receptor type II, BMP-2, and BMP-7 proteins. Treatment with the 3-hydroxy-3-methylglutaryl coenzyme A inhibitor lovastatin (34 microM) increased BMP-2 gene transcription >14-fold as measured by real-time PCR analysis (P<0.05 vs. solvent control). Moreover, VSMC proliferation stimulated with native low-density lipoprotein (100 microg of protein/mL) was prevented by either human recombinant BMP-2 or BMP-7 at concentrations of 100 ng/mL (P<0.05). Both BMPs also inhibited basal cell proliferation (P<0.05). Induction of BMPs and subsequent inhibition of VSMC growth and/or induction of vascular bone formation could contribute to the mechanisms by which statins increase plaque stability in patients with coronary atherosclerosis.