NT Devika1, BM Jaffar Ali2
1AU-KBC Research Centre, M.I.T.Campus, Anna University, Chrompet, Chennai 600044, India.
2Centre for Green Energy Technology, Pondicherry University, Puducherry 605 014, India.
ABSTRACT
A systems biology framework has been put forth to study the simulation of endothelial nitric oxide signaling in arterial endothelium. Endothelial cells lining the blood vessels are constantly exposed to variety of mechanical and chemical stimuli. In this study we investigate the two well known chemical and mechanical stimuli of the endothelium, namely VEGF and Shear Stress which modulates vascular function in physiological and pathological conditions. VEGF and shear stress activate similar downstream signaling molecules, including PI3-kinase, phospholipase, protein kinases, second messengers, and finally converging to eNOS phosphorylation at their respective residues. A generic model containing 61 molecular species, 34 mass action reactions, 10 enzymatic reactions, and one channel has been built to capture the calcium dependent and calcium independent regulation of eNOS activation mediated by VEGF and Shear stress. Specifically, we have investigated the role of different input stimuli as well as their dynamics along with key inhibitory factors in the eNOS activation. Analyses of the model reveal that VEGF and shear stress induced a different pattern of eNOS activation, maintaining signaling specificity of respective pathway. We quantify their contribution to eNOS activation by Ca independent and Ca dependent pathways. By maintaining the residue-dependent eNOS phosphorylation pool, we demonstrate the fine control in the in-silico dissection of pathway and its relevance in the understanding of differential downstream response leading to NO release. We discuss implication of these findings in advancing the understanding on systemic blood pressure, vascular remodeling and angiogenesis processes in general and NO mediated smooth muscle relaxation and contraction processes in particular. Read more…
