Diabetes Mellitus (DM) and periodontal diseases (PD) are complex chronic diseases with an established
bidirectional relationship. People with PD have two to three times the risk of having a heart attack, stroke, or
serious cardiovascular complications. PD in individuals with diabetes contributes to aggravated inflammatory
response leading to vascular disease (VD). Our group has previously shown that PD increases coronary heart
disease in diabetic patients. Nitric oxide (NO) mediated endothelial dysfunction is the initial step in the
development of VD. Reduced NO bioavailability due to the lack of tetrahydrobiopterin [BH4, a cofactor for
endothelial nitric oxide synthase (eNOS)], resulting in eNOS uncoupling, increases oxidative
stress/inflammation, impaired vascular smooth muscle relaxation and contributes to CV pathologies in diabetic
patients and rodent models of diabetes. Our previous studies demonstrated that chronic periodontal infection
reduced circulatory BH4 and NO levels and this reduction correlated with impaired immune signaling. In addition,
decreased levels of nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-dependent antioxidants and increased
levels of reactive oxygen species (ROS) also play a critical role in hypertension and vascular function. We
recently reported that primary human aortic endothelial cells (pHAECs) infected with Porphyromonas gingivalis
(Pg, a major periodontal pathogen), exhibited reduced cell viability, elevated pro-inflammatory cytokines,
reduced Nrf2/eNOS and BH4 biosynthesis. In addition, our in-vivo rodent studies demonstrate that chronic
polybacterial periodontal infection [Pg, Treponema denticola (Td), and Fusobacterium nucleatum (Fn), a model
of PD in humans] reduced the protein expression of Nrf2/BH4/nNOS in resistance blood vessels of the infected
mice. However, the specific mechanisms that contribute to aggravated inflammation and oxidative stress during
PD and diabetes leading to endothelial dysfunction is completely unknown. Our central hypothesis is that BH4
regulates NO-mediated vascular function, which is greatly impaired in diabetic PD compared to diabetes or PD
alone. The specific aims are,1: To determine whether hyperglycemia (HG) aggravates PD-induced impairment
in BH4/NOS and NO downstream signaling in pHAECs. 2: To investigate whether increased endogenous BH4
biosynthesis suppresses PD/T2DM induced inflammation, oxidative stress and restores eNOS activity, NO
synthesis, and NO mediated vascular relaxation. The proposed studies will be the first to determine the role of
periodontal pathogens in NO-mediated vascular function in T2DM animal models. The research outlined in these
aims has translational relevance, as it has the potential to identify novel treatment; options for PD/T2DM induced
VD.