November 11, 2014

Weill Cornell Study Reveals More About How Our Blood Vessels Develop and Grow

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Our blood vessels are the highways of our body. Block them, damage them or build new ones in the wrong place, and our health goes awry. Damage and unwanted growth of blood vessels underlie numerous diseases, from age-related macular degeneration, sickle cell anemia and cerebral malaria, to certain types of cancer.

By studying how blood vessels form from pre-existing blood vessels, a process known as angiogenesis, Prof. Timothy Hla, pathology and laboratory medicine at Weill Cornell Medical College, aims to understand and target the main players that cause or aggravate such diseases.

One of these main players is a type of fat molecule called Sphingosine 1-Phosphate, or S1P. According to Hla, who is also the Director of the Center for Vascular Biology, S1P is a naturally occurring molecule found in the cell membranes of numerous organisms.

Previously, Hla and his colleagues found that S1P is required for proper angiogenesis during the formation of the embryo, or embryogenesis.

New blood vessel formation during embryogenesis is crucial, according to Hla. As the embryo rapidly forms, it needs a large supply of nutrients and oxygen — all of which require functional blood vessels.

“The provision of S1P by red blood cells appears to be essential for the embryo to develop because if they cannot do that, the blood vessels that are being formed in the embryo become unstable [and] leaky, and the embryos hemorrhage and die,” Hla said.

As published in the September issue of the Journal of Clinical Investigation, Hla and his research team discovered that S1P is exclusively secreted by red blood cells during the formation of the embryo.

“Through this research, we were able to show that red cells communicate with developing blood vessels to complete their development. That has never been identified before,” he said.

Hla and his team, including primary author and post-doctoral fellow Yuquan Xiong, used mouse models to investigate the effects of blocking S1P production in red blood cells.

Using what is called, “tissue-specific gene knockouts,” the researchers were able to block S1P production in only a specific cell type — namely, red blood cells.

“Using this technology, we can use knockout mice in which only the red cells are deficient in making S1P, and then we can assess what happens in these mice,” Hla said.

The ability to solely block S1P production in red blood cells was crucial in making conclusions about the role of red blood cells and S1P in blood vessel growth. Hla and his team also used fluorescent microscopy to examine detailed changes in blood vessels.

“[This technology] allows us to understand the cross-talk between the red blood cells and the blood vessels, so this is really the first time that red blood cells were shown to influence angiogenesis,” Hla said.

According to Hla, many diseases originate from or are made worse by the malfunctioning of red blood cells and abnormal blood vessels.

For example, the genetic disease sickle cell anemia affects formation of red blood cells, and in cerebral malaria, the parasite infects the red blood cell and makes the cell abnormal.

“In many cases, even though the body can make more red cells, these diseases actually damage the blood vessels in different organs. In sickle cell crisis, your lungs get damaged. In cerebral malaria, your blood vessels in the brain get damaged — they clog up and the brain cells get starved of oxygen,” Hla said. “Such diseases lead to blood vessel abnormalities, and our work suggests that this lipid molecule, S1P, may be involved.”

Abnormal blood vessel growth is also known to be involved in certain types of cancer. Excess cancer cell growth requires excess nutrients, and a demand for more nutrients requires more blood vessel growth.

“Most of our cells in our body play by the rules of the organs — the liver only grows to a certain size, the lungs only grow to a certain size — but the cancer cells don’t obey these rules,” Hla said. “They start proliferating and invade different sites, and in order for them to grow and invade, they need nutrients to make more cells. You need new blood vessels for that.”

Although there are approved cancer-fighting drugs that target angiogenesis, their effect is not as “profound” as one would expect, according to Hla.

“That is why we need to understand the process of angiogenesis much better […] if we understood the major regulators then we can go after them to control disease associated angiogenesis,” Hla said.