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Mechanisms of vascular stabilization by PDGF-BB

Bovo, Emmanuela. Mechanisms of vascular stabilization by PDGF-BB. 2018, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12911

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Abstract

Peripheral artery disease is a chronic condition characterised by the narrowing of peripheral arteries due to atherosclerotic plaques and subsequent decrease in blood supply. The disease mainly affects the lower limbs and it manifests clinically as limb claudication in the early stages and can progress to a more severe form characterized by rest pain and tissue loss. Morbidity and mortality are high amongst individuals affected by the disease and although lifestyle changes and medical therapy have shown some efficiency, surgical and mini-invasive revascularization are still the mainstays of treatment. Novel strategies should be investigated in order to promote the formation of new collateral arteries (arteriogenesis) and/or capillaries (angiogenesis) and restore blood flow. Vascular Endothelial Growth Factor (VEGF) is the master regulator of angiogenesis, and its delivery in ischemic tissues has been associated with improved collateral artery development. However, its therapeutic potential is challenged by the need to control both the dose and duration of expression: sustained and uncontrolled levels cause the growth of angioma-like structures, whereas transient delivery shorter than about 4 weeks is insufficient for stabilization and persistence of induced vessels. We previously found that: 1) increasing VEGF doses impair vessel stabilization by inhibiting the endothelial Semaphorin3A/Neuropilin1+ monocytes (NEM)/TGF-b1 paracrine axis, and 2) PDGF-BB co-expression restores normal angiogenesis despite high VEGF levels.
Here we investigated whether and how PDGF-BB accelerates the stabilization of VEGF dose-dependent angiogenesis. For this purpose, mouse muscles were implanted with monoclonal myoblast populations homogeneously producing low, medium or high VEGF levels, with or without PDGF-BB. VEGF signaling was abrogated after 2 and 3 weeks by systemic treatment with the receptor-body Aflibercept. As expected, increasing VEGF doses progressively impaired stabilization. PDGF-BB co-expression did not change the effects of low and medium VEGF, but it greatly accelerated vascular stabilization at high VEGF (80% at 3 weeks vs 0% with VEGF alone). Aberrant vascular structures were switched to normal pericyte-covered capillaries, similar to those induced by low VEGF alone. However, stabilization was significantly greater than with low VEGF (50%), suggesting pericyte restoration may not be the only mechanism. Moreover, PDGF-BB dose-dependently stimulated endothelial Sema3A expression in vitro and restored Sema3A production, NEM recruitment and TGF-b1 level in vivo despite high VEGF levels. These results suggest that PDGF-BB dose-dependently accelerates vascular stabilization independently of pericytes recruitment through Sema3A expression and the NEM/TGF-b1 axis.
In conclusion, PDGF-BB co-delivery has the potential to overcome the limitations of VEGF gene delivery (dose and duration), providing a rational strategy to improve the clinical outcome of patients with limb ischemia.
Advisors:Affolter, Markus and Banfi, Andrea and Christofori, Gerhard M.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Cell Biology (Affolter)
UniBasel Contributors:Affolter, Markus and Banfi, Andrea and Christofori, Gerhard M.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12911
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (126, 3 Seiten)
Language:English
Identification Number:
Last Modified:29 Dec 2018 05:30
Deposited On:28 Dec 2018 10:06

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