Lowering Homocysteine Decreases Levels and Expression of VEGF₁₆₅ and Endostatin

Background

Homocysteine, vascular endothelial growth factor (VEGF), and endostatin have been implicated in angiogenesis and in the development and progression of atherothrombotic vascular disease. We sought to determine whether homocysteine modulates plasma levels of VEGF and endostatin and their expression in leukocytes in patients with peripheral arterial disease (PAD) or diabetes mellitus (DM).

Materials and methods

Ten patients with PAD and 15 patients with type 2 DM were evaluated before and 6 wk after oral administration of folic acid and B vitamins. Evaluation included measurements of plasma levels of homocysteine, VEGF, and endostatin by enzyme-linked immunosorbent assay and the expression of VEGF and endostatin mRNAs in leukocytes using RT-PCR. The measurements were compared with baseline findings in 12 healthy subjects.

Results

Basal homocysteine (P < 0.001) and VEGF (P < 0.01) levels were elevated in all patients versus healthy subjects. Basal endostatin levels were lower in patients with PAD but were higher in patients with DM compared with healthy subjects (P < 0.001). In patients with PAD or DM, folic acid and B vitamins administration resulted in significant reduction (P < 0.001) of plasma levels of homocysteine (20.9% and 26.2%), VEGF (29.7% and 40.4%) and endostatin (9.4% and 5.7%), respectively. Moreover, VEGF and endostatin mRNA expression in leukocytes was down-regulated in all patients after B vitamins and folate treatment.

Conclusion

These findings demonstrate that lowering of homocysteine with B vitamins and folic acid resulted in substantial reduction of plasma levels of VEGF but minimal reduction of endostatin and in down-regulation of their expression in leukocytes in patients with PAD or DM.

Key Words: peripheral arterial disease, diabetes mellitus, homocysteine, vascular endothelial growth factor, endostatin, angiogenesis