Scientists discover why some angiogenic drugs cause vascular pathology

Our vascular system provides oxygen and nutrients to all the tissues and organs in our body. However, they are not mere passive conduits for blood flow, but rather contribute to the physiology and homeostasis of all tissues and organs throughout our lives. Most of our blood vessels are inactive, but they express many genes to maintain this state, including genes for the Delta ligand-mediated gene pathway and Notch receptors.

In recent years, different pharmacological compounds have been developed whose objective is to block or induce the formation of new blood vessels (angiogenesis) in cases of cardiovascular diseases or cancer.

A group of these compounds used in clinical practice are those that inhibit different components of the Delta-Notch signaling pathway, a very important pathway for angiogenesis, but also for maintaining our blood vessels in an inactive state. These compounds, by intervening in the growth of blood vessels, have been shown to efficiently block tumor growth. In addition, it has been verified that they are capable of inducing angiogenesis in ischemic tissues, and with this, improve tissue regeneration and function.

However, these pharmacological compounds also cause vascular toxicity in other organs without previous diseases, such as the liver or the heart, which is why clinical interest in them has decreased.

Until now, it was thought that this toxicity was due to the activation of the expression of genes that promote angiogenesis and that lead to the appearance of neoplasms or tumors in the blood vessels.

Now, a new study, carried out by the team from the National Center for Cardiovascular Research (CNIC) led by Rui Benedito, has revealed that the molecular and cellular effect of some drugs used to modulate the formation of new blood vessels (angiogenesis), in diseases cardiovascular diseases or cancer, is not the cause of the vascular toxicity and pathophysiology that they cause in some patients.

“The study shows for the first time that the expression of genes involved in angiogenesis and the detected neoplasms is not what causes the vascular problems and pathologies that can arise after treatment,” says Rui Benedito.

Thanks to the use of advanced mouse genetic models, high-resolution confocal microscopy, as well as single-cell sequencing techniques, and proteomics, Rui Benedito’s group has discovered that the vascular toxicity associated with these pharmacological compounds is due to a change in vascular architecture, which prevents proper blood flow.

(Images: CNIC)

Researchers have shown that these changes in vascular architecture occur even when cell activation and expression of angiogenesis-related genes are blocked.

Therefore, explains Rui Benedito, “although neoplasms and the expression of genes related to angiogenesis are associated with changes in vascular architecture, they are not the cause of this change.”

Researcher Macarena Fernández Chacón, first author of the study, points out that “after analyzing different genes and pharmacological compounds directed against blood vessels, we have found new ways to control pathological angiogenesis without significantly affecting the vascular architecture of other organs and therefore therefore, without producing toxicity”.

The study is titled “Incongruence between transcriptional and vascular pathophysiological cell states”. And it has been published in the academic journal Nature Cardiovascular Research. (Source: CNIC)