Periodic Reporting for period 1 - TONEURENDO (In search for endothelial mechanisms of TPO-induced neuroprotection)
Reporting period: 2015-04-01 to 2017-03-31
The overall objective of this project is to fill the significant gap in early detection, prevention and treatment of VCI. This will be achieved by explaining microvascular mechanism of protective effects of thrombopoietin (TPO) in a novel unique mixed-risk animal model of VCI- specific to hypertension plus carotid-artery hypoperfusion (HH-VCI).
Given increased number of progenitor endothelial cells after TPO treatment, it is hypothesizes that protective effect of TPO is mediated by endothelium. Furthermore, protective effect of TPO is expected to be caused by activation of neoangiogenesis, anti-inflammatory and vasoprotective mechanisms driven by TPO action on endothelial. This hypothesis will be tested in two stages first, in-vitro and second, in-vivo. In-vitro models, will be used to investigate endothelial response to TPO in terms of its modulation of inflammatory response angiogenic potential and vasoprotective mechanisms. In-vivo models of TPOR KO mice and HH-VCI mice will be used to validate and confirm mechanisms identified in in vitro stage of experiments.
Project results indicate that VCI develops in very early stages of heart failure development, earlier that it was recognized so far and based on different pathomechanisms. Identified VCI pathology develops due to brain vessels disease related to endothelial inflammation and endothelial dysfunction.
Identified protective TPO mechanisms were discovered to be mediated via TPO receptor, hence TPO receptor blockage or dysfunction abolishes all identified TPO actions. Identified TPO actions include stimulation of new vessel formation- neoangiogenesis; increased vascular response to constriction; increased metabolic response of endothelial cells; and alteration in endothelial NO synthesis.