Vascular cells can reprogram themselves when the main pathway for their growth is blocked
Microscopy image of retinal blood vessels showing that mutant endothelial cells (red: VEGFR2-knockout) can grow in venous vessels (V), even in the absence of VEGF-VEGFR2 signalling - a pathway previously considered essential for angiogenesis. This demonstrates that endothelial cells can adapt and form vessels independently of VEGFR2. Turquoise-coloured nuclei (without red stain) represent wild-type cells.
© Irene Garcia-Gonzalez (CNIC) and Susana Rocha (CNIC/MPI Münster)
To the point
- Alternative pathway: Blood vessels can grow even when the VEGF-VEGFR2 signaling pathway is targeted -which was previously considered essential for vascular growth.
- Venous reprogramming: When this pathway is blocked, vascular cells adapt: They change their identity and become venous cells, which enables them to grow in the absence of VEGF signalling. This process enables the survival and long term growth of blood vessels-even within tumors.
- Possible mechanism for resistance: The discovery may explain why anti-cancer drugs targeting the VEGF pathway often lead to resistance and fail-and opens up new avenues for combination therapies targeting the identified venous genetic programmes.
In cancer research, anti-angiogenic drugs are used with the aim to block blood vessel growth (angiogenesis) in order to inhibit the tumor growth and metastasis. However, tumors develop resistance to these therapies over time - a major problem in cancer treatment.
Researchers at the Max Planck Institute for Molecular Biomedicine and the Centro Nacional de Investigaciones Cardiovasculares in Madrid have now demonstrated that when the classic VEGF-VEGFR2 signalling pathway is blocked, endothelial cells - which line the inside of blood vessels - adapt: they change their identity and become venous cells that grow independently of VEGF. This process, known as 'venous genetic reprogramming', enables vessels without VEGF signalling to grow inside organs and tumors.
How the researchers made this discovery
Until now, the signaling provided by the vascular endothelial growth factor (VEGF) and its receptor VEGFR2 was considered essential for the formation of new blood vessels-especially in tumors. That is why many cancer drugs aim to block this pathway. However, in many patients, resistance develops over time and the tumor continues to grow.
To understand how blood vessels can survive and grow despite the blockade of the VEGFR2 pathway, the research team developed a novel genetic mosaic technique- a method which, for the first time, makes it possible to compare healthy vascular cells and those lacking VEGFR2 signalling directly within the same organism and tumor. In this approach, both cell types grow side by side, are labeled with different colors, and can be tracked over long periods of time-from embryonic development through adulthood.
The method was developed by the team of Rui Benedito and enables an unprecedented level of resolution in functional genetics: "We can now very precisely analyze and quantify how mutated cells behave compared to normal cells over long periods of time," explains Rui Benedito. This revealed that over time certain mutant cells become prevalent in veins and small blood vessels, and continue to grow and proliferate despite the complete absence of VEGF-VEGFR2 signaling.
The surprise: Cells change their identity
The key discovery: The vascular cells that lost the VEGFR2 pathway altered their genetic makeup over time. They adapted and "transformed" into venous cells-a process the researchers call "venousization or venous reprogramming." This genetic reprogramming was crucial for the mutant cells' survival and their ability to form new blood vessels.
In addition, two other receptors-VEGFR1 and VEGFR3-played also a supporting role. They helped the cells move and survive when the main VEGF-VEGFR2 pathway was missing.
Why this may be important for people with cancer
The findings explain why anti-angiogenesis drugs used in cancer, that block only the VEGF-VEGFR2 pathway, often have only a temporary effect. "When only one pathway is targeted for long periods of time, vascular cells have time to adapt and find alternative ways of growing. This is natural selection in action, with the fittest cells eventually becoming dominant", says Rui Benedito, who has been working at the Max Planck Institute for Molecular Biomedicine in Münster since June 2025 and led the study. "If we block just one pathway, the cells find another. To achieve a lasting effect, we must block multiple pathways simultaneously."
The Future: New Therapies Through Combination
The identification of how blood vessels can grow in the absence of VEGF signalling offers new hope: Future anti-angiogenesis and anti-cancer therapies could block several of these pathways at the same time-for example, through combinations of drugs that block VEGF-VEGFR2 signalling and the molecules responsible for the identified venous reprogramming.
"We now have a much better understanding of the alternative venous growth pathways, and so we can aim to specifically block them," says Benedito. "We expect the combination targeting to be much more effective."
