Proper vascular function is important for well-being of mother and growing fetus. VEGF_TOTAL, and VEGF_165b levels and its vascular endothelial complications in gestational diabetes mellitus (GDM) together with the association of inflammation and advanced glycation end products (AGEs) are less studied. VEGF_165b/VEGF_TOTAL (VEGF RATIO) in GDM pregnant women was investigated in this study. Plasma VEGF_TOTAL was lower in GDM (17.68 ± 1.30 pg/mL) compared to non-GDM (25.69 ± 1.40 pg/mL). VEGF_165b, ICAM-1, and AGEs were higher in GDM (9.9 ± 1.4 pg/mL, 201.04 ± 7.85 µg/mL, and 10.40 ± 0.98 µg/mL, respectively) and lower in non-GDM (6.47 ± 0.70 pg/mL, 174.1 ± 7.11 µg/mL, and 4.71 ± 0.39 µg/mL, respectively). Compared to non GDM (0.25 ± 0.02), VEGF RATIO was higher in GDM (0.45 ± 0.04) and correlated with -ICAM-1 (r = 0.375, p < .001) and AGEs (r = 0.199, p < .05). Tertile stratification of VEGF RATIO implied that frequency of GDM increases with increasing tertiles of VEGF RATIO (p for trend <.001). Association of VEGF RATIO with GDM was significant even after adjusting for AGEs (OR = 1.279, CI = 1.118–1.462, p < .0010) but it lost its significance when adjusted for ICAM-1 (OR = 1.006, CI = 0.995–1.017, p = .308). VEGF RATIO plays an important role in GDM in association with vascular inflammation.

Cardiovascular diseases (CVD) are still the prevailing cause of death not only in industrialized countries, but even worldwide. Type 2 diabetes mellitus (type 2 DM) and hyperlipidemia, a metabolic disorder that is often associated with diabetes, are major risk factors for developing CVD. Recently, clinical trials proved the safety of gliptins in treating patients with type 2 DM. Gliptins are dipeptidyl-peptidase 4 (DPP4/CD26) inhibitors, which stabilize glucagon-like peptide-1 (GLP-1), thereby increasing the bioavailability of insulin. Moreover, blocking DPP4 results in increased levels of stromal cell derived factor 1 (SDF-1). SDF-1 has been shown in pre-clinical animal studies to improve heart function and survival after myocardial infarction, and to promote arteriogenesis, the growth of natural bypasses, compensating for the function of an occluded artery. Clinical trials, however, failed to demonstrate a superiority of gliptins compared to placebo treated type 2 DM patients in terms of cardiovascular (CV) outcomes. This review highlights the function of DPP4 inhibitors in type 2 DM, and in treating cardiovascular diseases, with special emphasis on arteriogenesis. It critically addresses the potency of currently available gliptins and gives rise to hope by pointing out the most relevant questions that need to be resolved.

The process of arteriogenesis is severely compromised in patients with diabetes mellitus (DM). Earlier studies have reported the importance of Egr-1 in promoting collateral outward remodeling. However, the role of Egr-1 in the presence of DM in outward vessel remodeling was not studied. We hypothesized that Egr-1 expression may be compromised in DM which may lead to impaired collateral vessel growth. Here, we investigated the relevance of the transcription factor Egr-1 for the process of collateral artery growth in diabetic mice. Induction of arteriogenesis by femoral artery ligation resulted in an increased expression of Egr-1 on mRNA and protein level but was severely compromised in streptozotocin-induced diabetic mice. Diabetes mellitus mice showed a significantly reduced expression of Egr-1 endothelial downstream genes Intercellular Adhesion Molecule-1 (ICAM-1) and urokinase Plasminogen Activator (uPA), relevant for extravasation of leukocytes which promote arteriogenesis. Fluorescent-activated cell sorting analyses confirmed reduced leukocyte recruitment. Diabetes mellitus mice showed a reduced expression of the proliferation marker Ki-67 in growing collaterals whose luminal diameters were also reduced. The Splicing Factor-1 (SF-1), which is critical for smooth muscle cell proliferation and phenotype switch, was found to be elevated in collaterals of DM mice. Treatment of DM mice with insulin normalized the expression of Egr-1 and its downstream targets and restored leukocyte recruitment. SF-1 expression and the diameter of growing collaterals were normalized by insulin treatment as well. In summary, our results showed that Egr-1 signaling was impaired in DM mice; however, it can be rescued by insulin treatment.