Scientists Discover That Blood Vessels Remember Their Origins

Researchers have found a connection between a blood vessel cell’s ‘biography’ and its role in an adult organism.

Researchers discover that blood vessels can be tailored to specific purposes.

Our family history tends to influence our future in a variety of ways. The same is true for blood vessels, according to a Weizmann Institute of Science study that was recently published in Nature. The scientists found that blood vessels develop from unexpected progenitors and went on to demonstrate that the blood vessels’ unusual origin impacts their role in the future.

“We found that blood vessels must derive from the right source in order to function properly – it’s as if they remember where they came from,” says team leader Professor Karina Yaniv.

The blood vessels that serve various organs vary greatly from one another. For instance, the kidneys filter the blood, therefore the walls of their blood vessels contain tiny holes that allow the efficient passage of substances. In the brain, the same walls are practically hermetic, guaranteeing a protective blockage known as the blood-brain barrier. Similarly, the lungs’ blood channel walls are also well adapted for another function, aiding gaseous exchange.

Bone-forming (red) and lymphatic vessel (green) cells in a growing zebrafish fin. Credit: Weizmann Institute of Science

Despite the vascular system’s critical importance, it is still unclear what causes the differences between the numerous blood vessels. These vessels had previously been thought to develop from either pre-existing blood vessels or progenitor cells that eventually mature and specialize to produce the vessel walls. However, recent research conducted by postdoctoral scholar Dr. Rudra N. Das from Yaniv’s laboratory in the Immunology and Regenerative Biology Department found that lymphatic vessels, a previously unidentified source, can also lead to the formation of blood vessels. This third source was discovered in transgenic zebrafish whose cells were marked with newly developed fluorescent markers that allow for tracing.

“It was known that blood vessels can give rise to lymphatic vessels, but we’ve shown for the first time that the reverse process can also take place in the course of normal development and growth,” Das says. By tracing the growth of fins on the body of a juvenile zebrafish, Das saw that even before the bones had formed, the first structures to emerge in a fin were lymphatic vessels. Some of these vessels then lost their characteristic features, transforming themselves into blood vessels.

Lymphatic vessel cells in a fin of a juvenile zebrafish (blue, top) give rise to the entire blood vessel network of this fin in the adult (blue, bottom). Credit: Weizmann Institute of Science

This seemed inexplicably wasteful: Why hadn’t the blood vessels in the fins simply sprouted from a large nearby blood vessel? Das and colleagues provided an explanation by analyzing mutant zebrafish that lacked lymphatic vessels. They found that when lymphatic vessels were absent, the blood vessels did sprout in the growing fins of these mutants by branching from existing, nearby blood vessels. Surprisingly, however, in this case, the fins grew abnormally, with malformed bones and internal bleeding. A comparison revealed that in the mutant fish, excessive numbers of red blood cells entered the newly formed blood vessels in the fins, whereas in regular fish with lymphatic-derived blood vessels, this entry was controlled and restricted.

The scarcity of red blood cells apparently created low-oxygen conditions known to benefit well-ordered bone development. In the mutant fish, on the other hand, an excess of red blood cells disrupted these conditions, which could well explain the observed abnormalities. In other words, only those blood vessels that had matured from lymphatic vessels were perfectly suited to their specialized function – in this case, proper fin development.

Excessive numbers of red blood cells entered the newly formed blood vessels in the fins of mutant fish (right), whereas in regular fish (left), with lymphatic-derived blood vessels, this entry was controlled and restricted Credit: Weizmann Institute of Science

Since zebrafish, unlike mammals, exhibit a remarkable capacity for regenerating most of their organs, Das and colleagues set out to explore how a fin would regrow following injury. They saw that the entire process they had observed during the fins’ development repeated itself during its regeneration – namely, lymphatic vessels grew first, and only later did they transform into blood vessels. “This finding supports the idea that creating blood vessels from different cell types is no accident – it serves the body’s needs,” Das says.

(Left to right): Stav Safriel, Dr. Rudra N. Das, Prof. Karina Yaniv and Yaara Tevet. Credit: Weizmann Institute of Science

The study’s findings are likely to be relevant to vertebrates other than zebrafish, humans included. “In past studies, whatever we discovered in fish was usually shown to be true for mammals as well,” Yaniv says.

She adds: “On a more general level, we’ve demonstrated a link between the ‘biography’ of a blood vessel cell and its function in the adult organism. We’ve shown that a cell’s identity is shaped not only by its place of ‘residence,’ or the kinds of signals it receives from surrounding tissue but also by the identity of its ‘parents.’”

The study could lead to new research paths in medicine and human development studies. It might, for example, help clarify the function of specialized vasculature in the human placenta that enables the establishment of a low-oxygen environment for embryo development.

It could also contribute to the fight against common diseases: Heart attacks might be easier to prevent and treat if we identify the special features of the heart’s coronary vessels; new therapies may be developed to starve cancer of its blood supply if we know how exactly this supply comes about. Additionally, knowing how the brain’s blood vessels become impermeable may help deliver drugs to brain tissues more effectively. In yet another crucial direction, the findings may have application in tissue engineering, helping supply each tissue with the kind of vessel it needs.

Yaniv, whose lab specializes in studying the lymphatic system, feels particularly vindicated by the new role the study has revealed for lymphatic vessels: “They are usually seen as poor cousins of blood vessels, but perhaps it’s just the opposite. They might actually take precedence in many cases.”

The study was funded by the M. Judith Ruth Institute for Preclinical Brain Research. 

Reference: “Generation of specialized blood vessels via lymphatic transdifferentiation” by Rudra N. Das, Yaara Tevet, Stav Safriel, Yanchao Han, Noga Moshe, Giuseppina Lambiase, Ivan Bassi, Julian Nicenboim, Matthias Brückner, Dana Hirsch, Raya Eilam-Altstadter, Wiebke Herzog, Roi Avraham, Kenneth D. Poss and Karina Yaniv, 25 May 2022, Nature.
DOI: 10.1038/s41586-022-04766-2