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Molecular mechanisms of vascular maturation for therapeutic angiogenesis

Applicant Banfi Andrea
Number 127426
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cardiovascular Research
Start/End 01.10.2009 - 30.09.2012
Approved amount 361'782.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Molecular Biology

Keywords (16)

Therapeutic angiogenesis; Gene therapy; Pericytes; VEGF; PDGF-BB; Notch; Ephrins; Angiopoietins; TGF; Angiogenesis;; Pericytes;; Gene therapy;; TGFb.

Lay Summary (English)

Lead
Lay summary
Obstructions to blood flow in the vessels of the heart and the legs are the most common cause of death and disability in the western world. The aim of our studies is to develop strategies to grow new blood vessels to improve the flow in diseased areas. To do this we have delivered the genetic information for two substances which control the induction of new blood vessels (VEGF) and their stabilization (PDGF) into the muscle of mice. We have found in the previous funding period that PDGF can modulate the effects of VEGF and increase both its efficacy and safety. Delivering the genetic information, rather than the substances themselves, is necessary to ensure that they are continuously produced directly in the diseased tissue, without loss of therapeutic levels.In the current funding period we propose to extend these results along two lines: 1) to apply these biological concepts in a clinically applicable gene therapy strategy for therapeutic angiogenesis, and 2) to investigate the mechanism underlying the effects of PDGF-BB co-expression on VEGF actions. We will test the feasibility of delivering the genetic information directly to muscle tissue, without using cells, as a novel gene therapy strategy to achieve safe and efficacious blood vessel growth. This method would be more directly applicable to clinical practice. Further, PDGF modulates the effects of VEGF through the action of a specific cell type called pericyte and we will determine the molecules responsible for the actions of pericytes. The goal is to identify more specific targets that could be manipulated with drugs, so as to avoid the need of delivering cells and genetic material to diseased tissue.Our proposed research is motivated by the demand for improved treatment options for patients affected by ischemic cardiovascular diseases. The latest available statistics reveal that coronary artery disease affected 15.8 million people and peripheral artery disease 8 million in the USA in 2008 (American Heart Association website: www.americanheart.org/statistics). There is no medical therapy to halt or revert the process of atherosclerotic vessel obstruction. Surgery is often not feasible because of diffuse vessel disease or inacceptably high operative risk. Moreover, these long-lasting conditions have huge economic burdens for society, both in terms of lost productivity and healthcare costs. The American Heart Association estimates the total costs for coronary artery disease alone in 2009 at 165 billion dollars in the USA. The knowledge gained from the proposed research is expected to lead to the development of novel therapeutic angiogenesis strategies which could be applied to a large number of patients suffering from these diseases.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Long-term safety and stability of angiogenesis induced by balanced single-vector co-expression of PDGF-BB and VEGF164 in skeletal muscle
Gianni-Barrera Roberto, Burger Maximilian, Wolff Thomas, Heberer Michael, Schaefer Dirk J., Gürke Lorenz, Mujagic Edin, Banfi Andrea (2016), Long-term safety and stability of angiogenesis induced by balanced single-vector co-expression of PDGF-BB and VEGF164 in skeletal muscle, in Scientific Reports, 6, 21546-21546.
VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin-1+ monocyte/TGF- 1 paracrine axis
Groppa E., Brkic S., Bovo E., Reginato S., Sacchi V., Di Maggio N., Muraro M. G., Calabrese D., Heberer M., Gianni-Barrera R., Banfi A. (2015), VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin-1+ monocyte/TGF- 1 paracrine axis, in EMBO Molecular Medicine, 7(10), 1366-1384.
Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164
Sacchi V., Mittermayr R., Hartinger J., Martino M. M., Lorentz K. M., Wolbank S., Hofmann A., Largo R. A., Marschall J. S., Groppa E., Gianni-Barrera R., Ehrbar M., Hubbell J. A., Redl H., Banfi A. (2014), Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164, in Proceedings of the National Academy of Sciences, 111(19), 6952-6957.
Induction of aberrant vascular growth, but not of normal angiogenesis, by cell-based expression of different doses of human and mouse VEGF is species-dependent.
Mujagic Edin, Gianni-Barrera Roberto, Trani Marianna, Patel Abdulsamie, Gürke Lorenz, Heberer Michael, Wolff Thomas, Banfi Andrea (2013), Induction of aberrant vascular growth, but not of normal angiogenesis, by cell-based expression of different doses of human and mouse VEGF is species-dependent., in Human gene therapy methods, 24(1), 28-37.
Osteogenic graft vascularization and bone resorption by VEGF-expressing human mesenchymal progenitors
Helmrich Uta, Di Maggio Nunzia, Güven Sinan, Groppa Elena, Melly Ludovic, Largo Rene D., Heberer Michael, Martin Ivan, Scherberich Arnaud, Banfi Andrea (2013), Osteogenic graft vascularization and bone resorption by VEGF-expressing human mesenchymal progenitors, in Biomaterials, 34(21), 5025-5035.
The effect of controlled expression of VEGF by transduced myoblasts in a cardiac patch on vascularization in a mouse model of myocardial infarction
Marsano Anna, Maidhof Robert, Luo Jianwen, Fujikara Kana, Konofagou Elisa, Banfi Andrea, Vunjak-Novakovic Gordana (2013), The effect of controlled expression of VEGF by transduced myoblasts in a cardiac patch on vascularization in a mouse model of myocardial infarction, in Biomaterials, 34(2), 393-401.
VEGF over-expression in skeletal muscle induces angiogenesis by intussusception rather than sprouting.
Gianni-Barrera Roberto, Trani Marianna, Fontanellaz Christian, Heberer Michael, Djonov Valentin, Hlushchuk Ruslan, Banfi Andrea (2013), VEGF over-expression in skeletal muscle induces angiogenesis by intussusception rather than sprouting., in Angiogenesis, 16(1), 123-36.
Cell and Gene Therapy Approaches for Cardiac Vascularization
Melly Ludovic, Boccardo Stefano, Eckstein Friedrich, Banfi Andrea, Marsano Anna (2012), Cell and Gene Therapy Approaches for Cardiac Vascularization, in Cells, 1, 961-975.
Controlled angiogenesis in the heart by cell-based expression of specific vascular endothelial growth factor levels.
Melly Ludovic F, Marsano Anna, Frobert Aurelien, Boccardo Stefano, Helmrich Uta, Heberer Michael, Eckstein Friedrich S, Carrel Thierry P, Giraud Marie-Noëlle, Tevaearai Hendrik T, Banfi Andrea (2012), Controlled angiogenesis in the heart by cell-based expression of specific vascular endothelial growth factor levels., in Human gene therapy methods, 23(5), 346-356.
FACS-purified myoblasts producing controlled VEGF levels induce safe and stable angiogenesis in chronic hind limb ischemia.
Wolff Thomas, Mujagic Edin, Gianni-Barrera Roberto, Fueglistaler Philipp, Helmrich Uta, Misteli Heidi, Gurke Lorenz, Heberer Michael, Banfi Andrea (2012), FACS-purified myoblasts producing controlled VEGF levels induce safe and stable angiogenesis in chronic hind limb ischemia., in Journal of cellular and molecular medicine, 16(1), 107-117.
Generation of human MSC expressing defined xenogenic VEGF levels by optimized transduction and flow cytometry purification.
Helmrich Uta, Marsano Anna, Melly Ludovic, Wolff Thomas, Christ Liliane, Heberer Michael, Scherberich Arnaud, Martin Ivan, Banfi Andrea (2012), Generation of human MSC expressing defined xenogenic VEGF levels by optimized transduction and flow cytometry purification., in Tissue engineering. Part C, Methods, 18(4), 283-292.
Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB.
Banfi Andrea, von Degenfeld Georges, Gianni-Barrera Roberto, Reginato Silvia, Merchant Milton J, McDonald Donald M, Blau Helen M (2012), Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 26, 2486-2497.
Taming of the wild vessel: promoting vessel stabilization for safe therapeutic angiogenesis.
Reginato Silvia, Gianni-Barrera Roberto, Banfi Andrea (2011), Taming of the wild vessel: promoting vessel stabilization for safe therapeutic angiogenesis., in Biochemical Society transactions, 39(6), 1654-1658.
To sprout or to split? VEGF, Notch and vascular morphogenesis.
Gianni-Barrera Roberto, Trani Marianna, Reginato Silvia, Banfi Andrea (2011), To sprout or to split? VEGF, Notch and vascular morphogenesis., in Biochemical Society transactions, 39(6), 1644-1648.

Collaboration

Group / person Country
Types of collaboration
University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
International Kloster Seeon Meeting on Angiogenesis Poster VEGF over-expression in skeletal muscle induces intussusception, and not sprouting, by synchronous activation of endothelial Notch-1 and vascular enlargement. 15.09.2012 Kloster Seeon, Germany Djonov Valentin; Banfi Andrea; Reginato Silvia; Barrera Roberto Gianni;
International Vascular Biology Meeting Talk given at a conference VEGF dose negatively regulates the stabilization of newly induced vessels by inhibiting the Sema3A/Nrp1+CD11b+ monocytes/TGF-β1 axis. 02.06.2012 Wiesbaden, Germany Barrera Roberto Gianni; Banfi Andrea; Reginato Silvia;
Frontiers in Cardiac and Vascular Regeneration Talk given at a conference VEGF over-expression in skeletal muscle induces vascular enlargement and intussusceptive angiogenesis through reciprocal activation of Notch-1 in contiguous endothelial cells. 30.05.2012 Trieste, Italy Banfi Andrea; Barrera Roberto Gianni; Reginato Silvia; Djonov Valentin;
Cardiovascular Biology and Clinical Implications Meeting Poster Coordinated co-expression of PDGF-BB accelerates stabilization of VEGF164-induced angiogenesis 06.10.2011 Muntelier, Switzerland Banfi Andrea; Barrera Roberto Gianni; Reginato Silvia;
Gordon Research Conference on Angiogenesis Poster VEGF164 over-expression in skeletal muscle induces simultaneous activation of Notch-1 in contiguous endothelial cells, vascular enlargement and intussusceptive angiogenesis. 21.08.2011 Newport, RI, United States of America Barrera Roberto Gianni; Reginato Silvia; Banfi Andrea; Djonov Valentin;
Advances in the Cellular and Molecular Biology of Angiogenesis Poster Delta/Notch signaling pathway mediates in skeletal muscle intussusceptive angiogenesis induced by the over-expression of VEGF164 27.06.2011 Birmingham, Great Britain and Northern Ireland Barrera Roberto Gianni; Banfi Andrea; Reginato Silvia;
International Symposium on the Biology of Endothelial Cells Talk given at a conference The VEGF and PDGF-BB signalling balance determines the switch between normal and aberrant angiogenesis. 15.06.2011 Zurich, Switzerland Banfi Andrea; Barrera Roberto Gianni;
European Society of Cell and Gene Therapy Poster Dose-dependent angiogenesis by VEGF is species-specific 22.10.2010 Milano, Italy Banfi Andrea; Barrera Roberto Gianni;


Associated projects

Number Title Start Funding scheme
143898 Cellular and molecular mechanisms of vascular maturation for therapeutic angiogenesis 01.10.2012 Project funding (Div. I-III)
114056 Targeting of vascular maturation for therapeutic angiogenesis 01.10.2006 Project funding (Div. I-III)

Abstract

Background. Ischemic cardiovascular disease is the most common cause of death in the western world and, despite advances in medical and surgical therapy, the morbidity and mortality remain very high. Therapeutic angiogenesis aims to induce the formation of new blood vessels to improve the perfusion of ischemic tissue in patients with end-stage coronary artery or peripheral arterial disease that are not amenable to other treatment options. Vascular Endothelial Growth Factor-A (VEGF) is the most potent and specific angiogenic factor and it has been tested in several clinical trials with a variety of delivery methods. However, preclinical studies clearly demonstrated that high doses of VEGF can also induce aberrant vascular structures which resemble cavernous hemangiomas and grow progressively. The results of placebo-controlled clinical trials have been disappointing and yielded mostly negative results. The main conundrum of VEGF delivery-based strategies for therapeutic angiogenesis is its apparently limited therapeutic window in vivo, such that low doses are safe, but mostly inefficient, and higher doses become rapidly unsafe.Rationale. Our previous results show that the transition between normal and aberrant angiogenesis takes place in an all-or-none fashion across a discrete threshold level of VEGF expression. However, we found that this threshold is not an intrinsic property of VEGF dose alone, but rather depends on the balance between angiogenic stimulation by VEGF and vascular maturation by PDGF-BB-mediated pericyte recruitment. Our results in the previous funding period show that coordinated co-expression of PDGF-BB and pericyte recruitment effectively improves both safety and efficacy of VEGF gene delivery, by inducing robust normal and homogeneous angiogenesis despite heterogeneous and high VEGF levels.Specific aims. In the current funding period we propose to extend these results along two lines: 1) to apply these biological concepts in a clinically applicable gene therapy strategy for therapeutic angiogenesis, and 2) to investigate the mechanism underlying the modulation of VEGF effects by PDGF-BB co-expressio. We will dissect the role of pericytes and specific pericyte-mediated signaling pathways in the normalization of VEGF-induced angiogenesis by PDGF-BB (Aim 1). Further, we will investigate whether dose-dependent co-expression prevents angioma growth and leads instead to normal capillary networks by regulating the signaling pathways that control the endothelial cell fate decision to become a sprouting tip cell or a circumferentially growing stalk cell (Aim 2). We will then test the feasibility of AV and AAV-based coordinated co-expression of VEGF and PDGF-BB as gene therapy strategies to achieve safe and efficacious angiogenesis (Aim 3).Experimental design. Monoclonal populations of retrovirally-transduced myoblast, which stably secrete different amounts of VEGF or VEGF+PDGF, will be used to achieve specific expression levels in skeletal muscle. We will then co-express specific molecules to block or activate specific pathways involved in the pericyte-endothelium and endothelium-endothelium cross talk. Finally we will test the applicability of VEGF+PDGF co-delivery to a clinically relevant delivery system using a bicistronic AV or AAV vector.Expected value of the proposed project. The proposed research is expected to provide the basic preclinical testing of a novel therapeutic angiogenesis strategy based on coordinated targeting of both vascular induction and maturation. Furthermore, these experiments are expected to dissect the mechanisms by which PDGF-BB signaling regulates endothelial cells and blood vessel growth and to identify alternative molecular targets, which might provide more specific therapeutic effects to modulate the dose-dependent effects of VEGF gene delivery.
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