Networking & Grants
Capacity project: ERC-like – type "Grant Support" - ID PNII-CT-ERC-2012–2014/ no.6. Circulating platelet microparticles and endothelial progenitor cells in vascular atherosclerosis: new pathophysiological and therapeutic implications. Project Director - Dr. Adriana Georgescu
Title: Circulating platelet microparticles and endothelial progenitor cells in vascular atherosclerosis: new pathophysiological and therapeutic implications
Project Director: Adriana Georgescu, Ph.D., Biophysicist, Principal Investigator I, Group Leader Department: Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology ‘Nicolae Simionescu’, Bucharest, Romania
Team: Nicoleta Alexandru, Ph.D., Miruna Nemecz, Ph.D., Irina Titorencu, Ph.D., Eugen Andrei, Ph.D.-student, Florentina Safciuc, Ph.D.
Project summary
Background: Atherosclerosis is an inflammatory disease, in which risk factors such as hyperlipidemia and hypertension affect the arterial endothelium, resulting in dysfunction, cell damage or both.
Purpose: The present study will be designed to investigate the dual behave of circulating platelet microparticles (PMPs) as biological effectors with important role in the vascular patho-physiology and as endogenous triggers of endothelial progenitor cells (EPCs) to facilitate endothelial repair and angiogenesis in vivo.
The major objectives: (1) to design new animal models, the hypertensive–hypercholesterolemic (HH) hamster, that mimics the atherosclerotic disease, and HH hamster injected with PMPs from HH hamster or EPCs from control (C) hamster, or PMPs and EPCs; (2) to investigate mechanistic insights by which atherosclerosis induces the endothelial dysfunction: a) ultrastructural changes; b) vascular wall inflammation, quantifying the protein expression of pro-inflammatory molecules (MMP3, MMP7, MMP9, MMP12, TIMP1, TIMP2, TIMP3); c) contractile and vasodilator response of arterial wall; d) alterations in number or function of PMPs and EPCs by analyzing specific markers on surface of PMPs (P-selectin, TF, vWF, APC, EPCR) and EPCs (VEGF, SDF-1, CXCR4, VEGFR1,2, B2Integrin, PSGL1); (3) to disclose the contribution of PMPs in inflammation and plaque progression by the effect on above mentioned pro-inflammatory specific molecules, in intraplaque thrombogenicity following the coagulation factors (TF, FVII , FX), and in mediating vascular dysfunction; (4) to explore EPCs capacity for the endothelial repair and restoration of vascular dysfunction; (5) to look at the mechanism by which EPCs influence the vasodilation of vascular wall after their attachment targeting Cox2, PGI2, cAMP molecules; (6) to search the paracrine effects of PMPs on EC activation and EPCs mobilization, adhesion and homing by studying the pro-inflammatory endothelial cytokines (SDF-1, CXCR4, VEGF, eNOS, RANTES, IL-6, IL-8, ICAM-1, VCAM-1, E-selectin, P-selectin) and pro-angiogenic markers (VEGFR2, VEGFR1, Tie-2, PIGF); (7) to evaluate the pathways through which PMPs regulate endothelial function and vascular haemostasis; phenotypic and functional characterization of PMPs following activated protein C (APC).
Materials and Methods: Thoracic aortas and mesenteric resistance arteries will be explanted from experimental animals; blood samples will be collected and the following techniques will be used: biochemical assays, blood pressure measurement, flow cytometry, electron and fluorescence microscopy, wire myography, immunoblotting, Elisa.
The expected results: (1) outlining an experimental design of atherosclerosis, including transplant of PMPs and EPCs; (2) essential role of PMPs in atherosclerosis development not only as an amplifier of endothelial dysfunction, but also by accelerating the progression of atherosclerotic lesion by promoting thrombogenicity and plaque growth; (3) contribution of EPCs to regenerate the vascular endothelial barrier; and (4) influence of PMPs in EPCs biological functions, including pro-inflammatory, thrombogenic and pro-angiogenic molecules.
Conclusion: A complete understanding of PMPs action mechanisms and of molecular mechanisms governing the repair ability of EPCs will open new insights for the development of novel therapeutic strategies to combat atherosclerosis.
Project Publications:
Peer-review ISI articles:
1. Nicoleta Alexandru, Eugen Andrei, Emanuel Dragan, Adriana Georgescu. Interaction of platelets with endothelial progenitor cells in the experimental atherosclerosis; the role of transplanted endothelial progenitor cells and platelet microparticles. Biology of The Cell, 107: 189–204, 2015.– impact factor 3,87.
2. Eugen Andrei, Nicoleta Alexandru, Emanuel Dragan, Adriana Georgescu. Flow cytometric analysis of circulating microparticles and endothelial progenitor cells in plasma; a research tool for atherosclerosis and therapy. Experimental and Clinical Cardiology, 20 (7): 1554-1563,2014.- impact factor 1.10
3. Elisabeta Bădila, Ana Maria Daraban, Silviu Ghiorghe, Adriana Georgescu, Nicoleta Alexandru, Daniela Bartoş, Cristina Tîrziu. Rethinking cardiovascular therapy - the effect of irbesartan on circulating microparticles and endothelial progenitor cells in patients with hypertension and dyslipidemia. Farmacia, 62 (1): 93-106, 2014.- impact factor 1.25
4. Adriana Georgescu, Nicoleta Alexandru, Miruna Nemecz, Irina Titorencu, Doina Popov.Irbesartan administration therapeutically influences circulating endothelial progenitor cell and microparticle mobilization by involvement of pro-inflammatory cytokines. European Journal of Pharmacology, 711: 27-35, 2013. - impact factor 2.78
5. Nicoleta Alexandru, Doina Popov, Emanuel Dragan, Eugen Andrei, Adriana Georgescu. Circulating endothelial progenitor cell and platelet microparticle impact on platelet activation in hypertension associated with hypercholesterolemia. PloS One, 8(1):e52058-e52068, 2013. - impact factor 4.092
6. Bich-Hoai Thi Ton, Qingmin Chen, Gisela Gaina, Catalin Tucureanu, Adriana Georgescu, Carmen Strungaru, Maria-Luiza Flonta, Dinah Sah, Violeta Ristoiu. Activation profile of dorsal root ganglia Iba-1 (+) macrophages varies with the type of lesion in rats. Acta Histochemica,115 (8): 840-850, 2013 [Epub ahead of print]. - impact factor 1,608
7. Nicoleta Alexandru, Adriana Georgescu. Circulating microparticles and microRNAs as players in atherosclerosis. World Journal of Hematology, 6; 2(2): 16-19, 2013.
8. Adriana Georgescu, Nicoleta Alexandru, Eugen Andrei, Irina Titorencu, Emanuel Dragan, Cristina Tarziu, Silviu Ghiorghe, Elisabeta Badila, Daniela Bartos, Doina Popov. Circulating microparticles and endothelial progenitor cells in atherosclerosis; pharmacological effects of irbesartan. Journal of Thrombosis and Haemostasis, 10: 680-691, 2012.- impact factor 6.4
9. I Titorencu, M. G. Albu, F. Anton, A. Georgescu, V. V. Jinga. Collagen – dexamethasone and collagen-D3 scaffolds for bone tissue engineering. Molecular Crystals and Liquid Crystals, 555: 1-10, 2012. - impact factor 0.502
10. Nicoleta Alexandru,Doina Popov, Adriana Georgescu. Platelet dysfunction in vascular pathologies and how can it be treated. Thrombosis Research, 129:116-126, 2012. – impact factor 2.44
Peer-review articles indexed in international database:
1. Nicoleta Alexandru, Elisabeta Badila, Adriana Georgescu. The role of endothelial progenitor cells in the cardiovascular disease pathogenesis. J Stem Cells Res, Rev & Rep.1(2): 1-2, 2014.
2. C.S. Stancu, A. Georgescu, L. Toma,G.M. Sanda, A.V. Sima. Glycated low density lipoproteins alter vascular reactivity in hyperlipidemic hyperglycemic hamsters; Annals of RSCB. 17(1), 9-15, 2012.
Books
1. Adriana Georgescu. Cardiovascular Dysfunction: New Biomarkers and Therapies. Published by Scholars' Press, OmniScriptum GmbH & Co. KG, Saarbrücken, Germany, ISBN -978-3-639-71643-6, 2014.
