Scientists of the National Center for Cardiovascular Research (CNIC) led by Rui Benedito have discovered a cellular and molecular mechanism that can be exploited to induce productive and sustained angiogenesis in tissues that have become ischemic due to reduced blood supply.

Until now, tissue regeneration treatments based on vascular growth factors have not succeeded in inducing effective angiogenesis—the process through which the body generates new blood vessels. The results, published in Nature Communications, suggest that it might be possible to manipulate the newly discovered mechanism to achieve optimal therapeutic angiogenesis.

Just as roads and highways connect cities and allow them to grow and operate, so the body’s blood vessels are essential for the development and function of tissues. Inhibition of vessel growth is an important therapeutic goal in cancer, whereas induction of angiogenesis has the potential to promote the formation of new blood vessels and tissue regeneration in cardiovascular disease.

Over the last 20 years, scientists have shown that appropriate growth of blood vessels in each tissue depends on a correct balance of several molecular proangiogenic and antiangiogenic mechanisms. Ischemic or hypoxic tissues secrete vascular endothelial growth factors (VEGF), which promote angiogenesis by inducing the proliferation and migration of vascular cells. Previous research by Rui Benedito’s group showed that blood vessel cells resist and oppose these external mitogenic cues through an intercellular ligand-receptor signaling mechanism called Notch.

The currently prevailing view is that increases in VEGF concentration or decreases in vascular Notch signaling stimulate both vascular cell proliferation and vessel growth. Therefore, strategies aimed at stimulating mitogenesis and angiogenesis to treat cardiovascular disease are based on drugs that promote VEGF signaling or block natural angiogenesis inhibitors such as Notch.

Using sophisticated genetic mouse models and cell imaging tools, Rui Benedito’s group have now discovered that the effect of these drugs and signalling mechanisms varies with the stage of angiogenesis and the vascular context.

The results in the Nature Communications study indicate that high mitogenic stimulation induced by VEGF (or Notch inhibition) arrests the proliferation of angiogenic vessels, while at the same time inducing the proliferation of more mature vessels, which are less important for effective angiogenesis in the context of disease. “The arrest of angiogenesis is due to a bell-shaped dose-response to the mitogenic stimulation. At high levels of mitogenic stimulus, the endothelial cells migrate and branch, but do not proliferate. Eventually, this affects the sustainable development of the blood vessels and the growth or regeneration of the surrounding tissues,” says Rui Benedito.

The newly identified mechanism could also explain the failure of several clinical trials seeking to boost angiogenesis in ischemic hearts after a myocardial infarction.

Rui Benedito says that the results “significantly increase our understanding of the biology of blood vessels and will enable us to design better therapeutic strategies to induce effective angiogenesis in injured or ischemic tissues.”

• Pontes-Quero, S., Fernandez-Chacon, M., Luo, W., Lunella, F. F., Casquero-Garcia, V., Garcia-Gonzalez, I., . . . Benedito, R. (2019). High mitogenic stimulation arrests angiogenesis. Nature Communications, 10(1), 2016. doi:10.1038/s41467-019-09875-7

One of the goals of the CNIC is to serve as a forum for the exchange of ideas in basic and translational cardiovascular research. To this aim, we organize every year advanced workshops - the CNIC Conferences –, to bring leading scientists together to discuss ‘hot’ topics of common interest. These conferences have a workshop format consisting of about 20 guest speakers and a limited number of participants (about 100). The participants will have the opportunity to present their work in poster sessions. This format enables an extensive discussion of current issues and controversies, and stimulates new thinking and ideas. The Conferences runs from Thursday late afternoon to Saturday lunchtime. 

The CNIC is organizing the next two CNIC Conferences:

2019 New Concepts on Age-Related Cardiovascular Disease - October 24-26. Organisers: V. Andrés, A. Hidalgo, JJ Fuster and A. Tall

2020 Cardiac Regeneration: from mechanisms to therapies - April 16-18. Organisers: M. Torres, N. Mercader, H. Sadek and M. Giacca

The first one, New Concepts on Age-Related Cardiovascular Disease, will cover four different topics of high relevance in the field: (1)  The Vascular-Neural-Immune axis in age-related diseases; (2) Somatic mutations and clonal hematopoiesis in cardiovascular disease; (3) The aging immune system in cardiovascular disease; (4) Cellular senescence and cardiovascular disease. The Conference will address the new trends in this area as well as potential strategies for exploiting this information therapeutically.

In the 2020 conference titled Cardiac Regeneration: from mechanisms to therapies, the mechanistic and physiological basis of cardiac regenerative ability will be extensively addressed from an evolutionary, developmental and physiological perspective.  The conference will include the latest advances in understanding the mechanisms underlying cardiac repair in naturally regenerating organisms and how can these be stimulated in non-regenerating mammals.  The conference will also review the current translational regenerative strategies, including gene therapy, modified nucleic acid administration, tissue engineering and cell reprogramming.  The forum will be an ideal setting for critically addressing the recent controversies in the field of cardiac stem cells and the failure so far in successful translation of experimental therapies into a clinical benefit.

More information soon at www.cnic-conference.com

The General Secretary of Scientific Coordination, Mr. Rafael Rodrigo, and the President of the Pro CNIC Foundation, Mr. Luis de Carlos, have formalized an agreement to renew the commitment acquired by the 12 private companies that constitute the Pro CNIC Foundation to continue participating in the National Center for Cardiovascular Research (CNIC), directed by Dr. Valentín Fuster, until the year 2028.

Thanks to this innovative example of public-private collaboration, the CNIC has established itself as a world leader in biomedical research. Hence, the CNIC has been awarded the Severo Ochoa accreditation in recognition of its international excellence in the field of research.

The Pro CNIC Foundation is an entity through which these 12 pioneering companies channel their contributions aimed at financing the CNIC, which has made it a benchmark for success in scientific patronage. In this Foundation we can find the solidarity interests of some of the most important companies in Spain: Acciona, Santander Bank, BBVA Bank, Endesa, Mapfre Foundation, Mutua Madrileña Foundation, Ramón Areces Foundation, Repsol Foundation, Inditex, "la Caixa", Prisa and Telefonica.

The patrons’ financing of the Pro CNIC Foundation enables the CNIC's research to have a direct impact on the care and improvement of the health of the general population. In addition, part of their innovations are converted into patents that generate an economic return and favor the development of R + D + I in Spain.

Three examples illustrate its contribution: On the one hand, the marketing of the polypill, developed by the CNIC, has already generated royalties of more than 1.5 million euros, making it the first drug approved in Europe for secondary cardiovascular prevention.

Cardiac imaging patent

Another example of translational research is the CNIC's new cardiac imaging patent, which has reduced magnetic resonance time from 40 minutes to less than one. This technology is essential to see the function and anatomy of the heart. The substantial reduction in time will have an important impact on the patient's well-being, the elimination of waiting lists and a more precise diagnosis for a larger number of patients. Finally, the biomarker for the diagnosis of acute myocarditis identified in the CNIC has allowed the development of a biosensor able to distinguish between acute myocarditis and a heart attack in only 30 minutes with a blood sample from the patient in order to be able to treat it adequately. The Pro CNIC joins together 12 of the most important companies in Spain: Acciona, Santander Bank, BBVA, Endesa, Mapfre Foundation, Mutua Madrileña Foundation, Ramón Areces Foundation, Repsol Foundation, Inditex, "la Caixa", Prisa and Telefónica.

Furthermore, thanks to the Pro CNIC Foundation it will be possible to continue to identify and train bright young people who show interest in science and research from early stages of their education and are already part of the quarry of researchers of excellence in our country.

In the words of Dr. Fuster, General Director of the CNIC, "this innovative public-private financing formula of the CNIC, which thanks to this agreement will continue until 2028, will allow the CNIC to remain a world leader in cardiovascular research and whose benefits are transferred directly to the patient.” From the CNIC, the relationship with the institutions that make up the Pro CNIC Foundation is highly valued: "We have shown that this is an effective and sustainable formula that, in short, guarantees excellence in cardiovascular research, the only way to move forward in the fight against what is the leading cause of death in developed countries and that will soon be in the poorest regions too", explains Dr. Fuster.

Meanwhile, the Minister of Science, Innovation and Universities, Pedro Duque, has expressed his satisfaction about this new impulse so that the National Center for Cardiovascular Research continues to promote translational research of excellence for the benefit of the patient and society.

The President of the Pro CNIC Foundation, Mr. Luis de Carlos, has given special thanks to the patrons for their constant involvement in the project and for their contribution to cardiovascular research. By the end of 2028, the companies of the Pro CNIC Foundation will have contributed more than 90 million euros to the project. According to D. Luis de Carlos, "it is great news for our country that this group of companies extends its commitment demonstrating once again, through scientific patronage, its involvement with both R & D & I, essential for the competitiveness of our country, as well as with the substantial improvement of the quality of life of all Spaniards”.

It is interesting to highlight that, within this innovative model, these companies not only contribute funds, but also collaborate in the decision-making and organization of the center through their participation in the Board of Trustees (Mapfre Foundation, Santander Bank, Telefónica and "La Caixa” Bank Foundation) and the Delegate Committee of the CNIC (Mapfre Foundation and Telefónica).

El Mundo: Especial Centros de Investigación en España