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In search for endothelial mechanisms of TPO-induced neuroprotection

Periodic Reporting for period 1 - TONEURENDO (In search for endothelial mechanisms of TPO-induced neuroprotection)

Reporting period: 2015-04-01 to 2017-03-31

Ageing is recognized as one of the greatest social and economical challenges of the 21century for European societies. With, Vascular Cognitive Impairment (VCI) being one of the leading causes of age-related cognitive impairment and one of the major causes of disability in the elderly. Although, the concept of VCI was introduced in 1993, current treatment is limited to management of vascular risks and symptomatic pharmacotherapy targeting vascular dementia.
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.
Major scientific output pertains to two major discoveries: identification of novel VCI model and identification of novel mechanism of TPO action on endothelium.
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.
Results of this project contribute new data to current knowledge on VCI mechanism. Novel mechanisms of TPO protective role may help in better understanding of processes underlying VCI development as well as in earlier detection and more effective treatment. Identification of yet unrecognized mechanism of VCI development in early stage of heart failure development provides rationale for update in treatment and diagnostics of patients with heart failure.