Vascular proliferation and transforming growth factor-β expression in pre- and early stage of diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats

The roles of transforming growth factor (TGF)-beta1 in vascular proliferation, atherosclerosis, and plaque still remain controversial. TGF-beta1 has been previously reported to inhibit the proliferation and migration of vascular smooth muscle cells and endothelial cells, in vitro. On the other hand, administration or transgenic overexpression of TGF-beta1 enhances extracellular matrix synthesis and Cellular hyperplasia of the intima and media in the normal artery and injured artery in vivo. We evaluated the correlation of arterial proliferation with plasma levels of TGF-beta1 and TGF-beta receptor tape II, respectively, in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new strain of spontaneous non-insulin-dependant diabetes mellitus (NIDDM) models. OLETF rats (n = 30) were divided into three groups aged 5, 15, and 30 weeks. Long-Dans Tokushima Otsuka (LETO) rats (n = 30) were used as age-matched non-diabetic controls. Plasma TGF-beta1 and insulin were determined by enzyme-linked immunosorbent assay. Immunoreactive TGF-beta receptor type II antigen was detected by immunohistochemistry on the thoracic artery. Arterial media area was measured microscopically. Oral glucose tolerance test was performed to examine the stage of diabetes mellitus. The thoracic aorta wall section area increased significantly from the age of 15 weeks in OLETF rats, versus LETO rats. In both OLETF and LETO rats, plasma TGF-beta1 increased significantly from the age of 15 weeks. In OLETF rats, plasma TGF-beta1 increased significantly over that in LETO rats (P < 0.001). Furthermore, TGF-beta receptor type II was detected on aortic wall as strong signals in OLETF rats, but only weakly in LETO rats. OLETF rats showed hyperinsulinemia and insulin resistance from the age of 15 weeks. With oral glucose tolerance test, from the age of 15 weeks, the high glucose level in OLETF rats was prolonged to 2 h after loading, and the insulin levels at both fasting and after loading were significantly higher than those of LETO rats (P < 0.001). There are significant linear relations between plasma TGF-beta1 antigen and aorta v, all section area, and plasma TGF-beta1 antigen and fasting insulin level (P < 0.001, respectively). We found that plasma TGF-beta1 and vascular TGF-beta type II receptors existed to a greater extent in pre- and earls stages of diabetes mellitus (DM) in OLETF rats compared with LETO rats. The greater extent of each in OLETF rats was associated with hyperinsulinemia and or vascular thickening. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.