Estimation of Vascular endothelial growth factor receptor-2 (VEGFR2), Disabled Homolog-2 (Dab-2) protein and Forkhead Box M1 (FOXM1) levels in saliva and serum in generalized periodontitis patients with and without Type 2 Diabetes Mellitus (T2DM)

Periodontal disease is one of the major problems encountered in patients with Type 2 diabetes mellitus (T2DM) which in turn is an important and independent risk factor for the development of periodontitis. While periodontitis represents a distant source of low-grade systemic inflammation and impaired metabolic control, on the other hand, microangiopathy and an increased angiogenic response, typical of T2DM, are correlated to the progression of periodontitis. Angiogenesis is also thought to be an essential process in the development of both these chronic inflammatory diseases.

Vascular endothelial growth factor (VEGF), a 45-kd homodimeric pro-inflammatory glycoprotein is a critical angiogenic factor that signals through VEGF receptors (VEGFRs). VEGF receptor 2 (VEGFR2) potentiates angiogenesis more potently than other VEGFRs. In diabetic conditions, there is a decrease in VEGF-induced phosphorylation of VEGFR2 and downstream signaling, leading to impaired angiogenesis. VEGF and VEGFR2 overexpression, as well as the great proliferation rate of endothelial cells observed in periodontitis suggest that angiogenesis in case of periodontal lesions is dependent on VEGF expression.

Disabled Homolog 2 (Dab2) is a highly conserved adaptor protein widely expressed in various tissues and primarily functions as a cytosolic, clathrin and cargo binding adaptor protein, with a pivotal role in endocytosis. Dab2 plays a direct role in regulating VEGF signalling in endothelial cells (ECs). It modulates EC migration and differentiation through a process named endothelial-to-mesenchymal transition (EndMT), which plays a key role in angiogenesis. Upregulation of Dab2 gene is seen in circulating lymphocytes and monocytes of periodontitis patients. Hyperglycemic ECs exhibit downregulation of Dab2 mRNA and protein levels, along with reduced expression of genes involved in cellular metabolism, growth, and proliferation.

Forkhead box protein M1 (FOXM1), belongs to the Forkhead family of transcriptional factors, is highly conserved & exerts regulatory control over Dab2 expression in endothelial cells during angiogenesis. Loss of FOXM1 is associated with upregulation of RANKL/OPG ratio. It also plays a crucial role in diabetes related cellular functions via beta cell proliferation, essential for pancreatic repair and insulin secretion.

To the best of our knowledge the roles of VEGFR2, Dab2 and FOXM1 have not been investigated together in patients with periodontitis and diabetes. Hence, the aim of this study is to evaluate the salivary and serum levels of VEGFR2, Dab2 and FOXM1 in patients with generalized periodontitis and type 2 diabetes mellitus.