Aorta tissues that were not exposed to BafA (left) did not sprout new vessels, while BafA-exposed aorta tissues (right) did. Photo credit: Dr. Kentaro Tsukamoto.
Research led by Dr. Kentaro Tsukamoto and Dr. Yohei Doi at the Fujita Health University in Japan identified the protein by which Bartonella henselae (B. henselae) induces angiogenesis.
This discovery provides insight into the mechanisms by which infectious bacteria can produce lesions in their hosts.
Findings of the Fujita Health University study, which also included the researchers naming the protein Bartonella angiogenic factor A (BafA), was published online ahead of print in the journal Nature Communications (July 16, 2020).
“We believe that BafA proteins can be leveraged as tools for studying angiogenesis, and we also consider potential medical benefits,” said Dr. Doj in a press release. “Most importantly, BafA is a potential target for the development of diagnostic and therapeutic strategies for bartonellosis.”
The study’s authors suggest that BafA proteins could be used in regenerative medicine.
Previous studies on B. henselae, the bacterium responsible for cat-scratch disease, have shown that it can directly “inject” proteins that inhibit apoptosis into the endothelial cells.
The researchers note B. henselae can also promote angiogenesis without directly contacting endothelial cells, which implies that the bacterium can secrete a bioactive substance that takes on the duty of kick-starting angiogenesis.
To begin their research, the study’s investigators introduced B. henselae into human endothelial cells in petri dishes, and observed that the bacteria caused the endothelial cells to multiply. To identify the genes that give B. henselae this ability, the researchers began inducing random mutations in the DNA of the bacteria and seeing whether the mutated bacteria could still make the endothelial cells multiply.
Through these experiments, the study’s authors determined that B. henselae can stimulate angiogenesis in human endothelial cells only if it possesses a functional copy of the gene that codes for, or guides the synthesis of, the BafA protein. They also found that exposing human endothelial cells to the isolated BafA protein caused the cells to multiply.
To confirm that BafA stimulates angiogenesis, researchers extracted samples of aorta from mice and placed the samples in gels that did or did not contain BafA. The aorta samples that were not exposed to BafA did not form new blood vessels, but the aorta samples that were exposed to BafA grew vessels that extended into the gel. The investigators also found that surgically placing a BafA-containing gel plug into living mice led to blood vessels growing from the surrounding tissue into the gel.
Further research with human endothelial cells in petri dishes showed that BafA activated cell surface receptors that recognize vascular endothelial growth factor. By binding to these receptors, BafA triggered the activation of a process inside the cells, involving proteins called mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERKs).
The MAPK/ERK pathway plays an important role in the multiplication of endothelial cells and angiogenesis.
“In the last set of experiments, we performed similar studies in a related bacterium called Bartonella quintana, the bacterium that causes trench fever, and we found that it produces its own version of BafA that also causes human endothelial cells to multiply,” Dr. Tsukamoto explained in the press release.
Further research is needed to confirm these findings, the investigators concluded.