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Cellular and molecular mechanisms of vascular maturation for therapeutic angiogenesis

Applicant Banfi Andrea
Number 143898
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 01.10.2012 - 30.09.2015
Approved amount 427'500.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Molecular Biology

Keywords (9)

VEGF; PDGF-BB; Therapeutic angiogenesis; Gene therapy; Ephrins; Notch; Pericytes; Skeletal muscle; In vivo imaging

Lay Summary (English)

Lead
The aim of our studies is to develop strategies to grow new blood vessels and improve perfusion in the heart and legs of patients with obstructed arteries. We propose to identify which molecular pathways regulate whether normal or aberrant blood vessels are induced by specific doses or combinations of vascular growth factors. Our results are expected to identify more specific targets to improve the treatment of many patients for whom current medical and surgical therapies are inadequate.
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 previously found that PDGF co-delivery can prevent the growth of aberrant blood vessels by VEGF and switch them to normal vascular structures. Now we propose to extend these results to investigate the mechanism underlying the effects of PDGF-BB co-expression on VEGF actions in order to identify more specific targets that could be exploited to avoid the unwanted effects of VEGF over-expression. 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 16.3 million people and peripheral artery disease 8 million in the USA in 2011 (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 unacceptably high operative risk. Moreover, these long-lasting conditions have huge economic burdens for society, both in terms of lost productivity and healthcare costs. 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: 12.11.2012

Responsible applicant and co-applicants

Employees

Publications

Publication
Engineered mesenchymal cell-based patches as controlled VEGF delivery systems to induce extrinsic angiogenesis
Boccardo Stefano, Gaudiello Emanuele, Melly Ludovic, Cerino Giulia, Ricci Davide, Martin Ivan, Eckstein Friedrich, Banfi Andrea, Marsano Anna (2016), Engineered mesenchymal cell-based patches as controlled VEGF delivery systems to induce extrinsic angiogenesis, in Acta Biomaterialia, 42, 127-135.
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.
Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine.
Martino M. M., Brkic S., Bovo E., Burger M., Schäfer D.J., Wolff T., Gürke L., Briquez P. S., Larsson H. M., Gianni-Barrera R., Hubbell J. A., Banfi A. (2015), Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine., in Front. Bioeng. Biotechnol., 3, 45.
VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin-1+ monocyte/TGF-β1 paracrine axis
Groppa Elena, Brkic Sime, Bovo Emmanuela, Reginato Silvia, Sacchi Veronica, Di Maggio Nunzia, Muraro Manuele G., Calabrese Diego, Heberer Michael, Gianni-Barrera Roberto, Banfi Andrea (2015), VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin-1+ monocyte/TGF-β1 paracrine axis, in EMBO Molecular Medicine, 7, 1366-1384.
VEGF, shear stress and muscle angiogenesis: A complicated triangle
Banfi Andrea, Banfi Andrea, Gianni-Barrera Roberto, Gianni-Barrera Roberto (2015), VEGF, shear stress and muscle angiogenesis: A complicated triangle, in Acta Physiologica, 214(3), 298-299.
Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164
Sacchi Veronica, Mittermayr Rainer, Hartinger Joachim, Martino Mikaël M., Lorentz Kristen M., Wolbank Susanne, Hofmann Anna, Largo Remo A., Marschall Jeffrey S., Marschall Jeffrey S., Groppa Elena, Gianni-Barrera Roberto, Ehrbar Martin, Hubbell Jeffrey A., Redl Heinz, Banfi Andrea (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 of the United States of America, 111(19), 6952-6957.
Split for the cure: VEGF, PDGF-BB and intussusception in therapeutic angiogenesis
Gianni-Barrera Roberto, Bartolomeo Mariateresa, Vollmar Brigitte, Djonov Valentin, Banfi Andrea (2014), Split for the cure: VEGF, PDGF-BB and intussusception in therapeutic angiogenesis, in Biochemical Society Transactions, 42, 1637-1642.
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), 5025-35.

Collaboration

Group / person Country
Types of collaboration
Dr. Holger Gerhardt, Cancer Research UK, London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Jeffrey A. Hubbell, EPFL, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Eduard Battegay, University Hospital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Martin Ehrbar, University Hospital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Congress of the European Society of Cell and Gene Therapy Talk given at a conference EphrinB2/EphB4 signaling controls the switch between normal and aberrant angiogenesis by VEGF 17.09.2015 Helsinki, Finland Banfi Andrea;
Tissue Engineering and Regenerative Medicine International Society World Congress Talk given at a conference Therapeutic Angiogenesis from Vascular Biology to Regenerative Medicine 08.09.2015 Boston, MA, United States of America Banfi Andrea;
Gordon Research Conference on Angiogenesis Poster EphrinB2/EphB4 signaling controls the switch between normal and aberrant angiogenesis by VEGF 02.08.2015 Newport, RI, United States of America Banfi Andrea;
Swiss Cardiovascular and Metabolic Research Conference Talk given at a conference Therapeutic angiogenesis by fibrin-based co-delivery of engineered VEGF and PDGF-BB proteins 22.01.2015 Fribourg, Switzerland Banfi Andrea;
American Heart Association Scientific Sessions Poster EphrinB2/EphB4 Signaling controls the Dose-Dependent Switch between Normal and Aberrant Angiogenesis by VEGF 15.11.2014 Chicago, IL, United States of America Banfi Andrea;
International Kloster Seeon Meeting Angiogenesis Poster EphrinB2/EphB4 signaling controls the switch between normal and aberrant angiogenesis by increasing VEGF doses 20.09.2014 Seeon, Germany Banfi Andrea;
Stem Cells in Development and Disease Talk given at a conference Normalization and accelerated stabilization of VEGF-induced angiogenesis by co-delivery of engineered PDGF-BB and VEGF proteins from fibrin matrices 09.09.2014 Basel, Switzerland Banfi Andrea;
Angiogenesis and Vascular Remodelling: New Perspectives Poster EphrinB2/EphB4 signaling controls the switch between normal and aberrant angiogenesis by increasing VEGF doses 14.07.2014 Chester, Great Britain and Northern Ireland Groppa Elena;
Tissue Engineering and Regenerative Medicine International Society European Meeting Talk given at a conference Normalization and accelerated stabilization of VEGF-induced angiogenesis by co-delivery of engineered PDGF-BB and VEGF proteins from fibrin matrices 10.06.2014 Genova, Italy Banfi Andrea;
American Society of Gene and Cell Therapy Poster Normalization and accelerated stabilization of VEGF-induced angiogenesis by co-delivery of engineered PDGF-BB and VEGF proteins from fibrin matrices 19.05.2014 Washington, DC, United States of America Banfi Andrea;
Swiss Society for Biomaterials and Regenerative Medicine Talk given at a conference Short-term co-delivery of fibrin-bound VEGF and PDGF-BB proteins ensures normalization and stabilization of VEGF-induced angiogenesis 07.05.2014 Basel, Switzerland Banfi Andrea;
Swiss Cardiovascular and Metabolic Research Conference Talk given at a conference VEGF induces Non-sprouting angiogenesis by VEGF requires contiguous activation of endothelial Notch1 throughand lateral induction of Dll4 expression. 16.01.2014 Fribourg, Switzerland Barrera Roberto Gianni; Groppa Elena; Banfi Andrea;
Gordon Research Conference on Angiogenesis Poster VEGF induces non-sprouting angiogenesis by contiguous activation of endothelial Notch1 and lateral induction of Dll4 expression. 04.08.2013 Newport, RI, United States of America Banfi Andrea;
Tissue Engineering and Regenerative Medicine International Society European Meeting Talk given at a conference Sustained and Highly Tunable Delivery of Engineered VEGF164 from Optimized Fibrin Matrices Ensures Normal, Stable and Functional Angiogenesis. 17.06.2013 Istanbul, Turkey Banfi Andrea;
Swiss Stem Cell Network Meeting Poster Sustained and highly tunable delivery of engineered VEGF164 from optimized fibrin matrices ensures normal, stable and functional angiogenesis. 08.02.2013 Bern, Switzerland Banfi Andrea;


Associated projects

Number Title Start Funding scheme
163202 The molecular switch between normal and aberrant angiogenesis by VEGF 01.10.2015 Project funding (Div. I-III)
127426 Molecular mechanisms of vascular maturation for therapeutic angiogenesis 01.10.2009 Project funding (Div. I-III)
150823 Serial block face SEM 01.12.2013 R'EQUIP
149581 New vascularization strategies for skin tissue engineering based on mechanisms of autologous skin graft taking 01.01.2014 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 1) VEGF overexpression in skeletal muscle at therapeutic doses induces angiogenesis by intussusception and not by sprouting; 2) Notch-1 regulates the initial stages of intussusception by a different pattern of activation compared to sprouting; 3) EphrinB2/EphB4 signaling is a crucial determinant of the switch between normal and aberrant angiogenesis by different VEGF doses.Specific aims. In the current funding period we propose to extend these results to investigate whether: 1) PDGF-BB co-expression induces normal angiogenesis by switching from intussusception to sprouting; 2) PDGF-BB normalizes aberrant VEGF-induced angiogenesis by preventing excessive Notch activation; and 3) stimulation of EphB4 signaling can prevent aberrant angiogenesis by high levels of VEGF alone.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.Expected value of the proposed project. The experiments proposed are expected to provide fundamental knowledge on the basic mechanisms by which pericyte recruitment regulates the dose-dependent effects of VEGF and the induction of normal or aberrant angiogenesis, identifying novel and possibly more specific molecular targets to modulate the effects of VEGF gene delivery for the treatment of ischemic diseases. One such target (EphrinB2/EphB4 signaling) will be tested for its therapeutic potential in a clinically relevant gene therapy approach.
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