Year: 2012
Type: dissertation
Abstract: Neurovascular remodeling has been recently recognized as a promising target for neurologic therapies. Hopes have emerged that, by stimulating vessel growth, it may be possible to stabilize brain perfusion, and at the same time promote neuronal survival, brain plasticity, and neurologic recovery. However, the key question remained whether increased vessel density leads to an increase in CBF, promoting recovery. Many studies in the recent past have demonstrated the beneficial effects of therapeutic angiogenesis but had minimum benefits for patients when translated into the clinics. Evaluation of readouts which are less relevant clinically and usage of animal models which sub-optimally mimic clinical situations might be responsible for these discrepancies. In order to understand whether the concept of induced angiogenesis is feasible from a pathophysiological point of view, we evaluated the temporal profile of capillary formation, after treating mice with VEGF and observed that new vessel formation indeed results in increased CBF and preservation of the brain energy state. Additionally, long term VEGF therapy rendered neuroprotection and better preservation of the BBB integrity. Evaluation of pericyte coverage confirmed the production of physiologically active vessels after VEGF therapy. Due to the potent, pleiotropic effects, VEGF might be a promising candidate for stimulating new vessel formation. Hyperlipidemia affects at least half the population of stroke patients while most of the experimental investigations are done in young and healthy animals with an intact vasculature. By utilising ApoE-/- mice that exhibit exacerbated atherosclerosis we show that hyperlipidemia compromises new vessel formation resulting in decreased CBF and disruption of brain metabolism after focal cerebral ischemia. Additionally, hyperlipidemia increased matrix disaggregation and counteracted pericyte coverage by decreasing N-cadherin expression. Our data underlines the necessity for experimental stroke investigations utilising clinically relevant animal models that also mimic risk factors such as hyperlipidemia so as to minimise the number of study failures.
Author: Anil Zechariah
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2282923908