Researchers have discovered a key molecular pathway that plays an important in angiogenesis, the growth of new blood vessels.
The study, led by Massimo Santoro, PhD, UCSF and Didier Stainier, PhD, UCSF professor of biochemistry and biophysics, was conducted on the zebrafish, the tiny, blue-and-silver striped denizen of India's Ganges River.
The team determined that two well known signalling molecules, birc2 and TNF, are vital to the survival of endothelial cells, which in zebrafish embryos line the blood vessels and maintain the integrity of the blood vessel wall during vascular development.
The birc2 gene belongs to a family of proteins that balances the control between cell survival and cell death (apoptosis). A cell, when it detects that it is irreparably damaged, induces apoptosis.
A dynamic balance between endothelial cell survival and apoptosis determines the integrity of the blood vessel wall.
The study included the examination of the zebrafish with unusual physical attributes in order to identify the mutated genes that were responsible for the traits.
"We began with a genetic mutant that displayed vascular haemorrhage associated with vascular defects, and soon proved that the mutant had a defective birc2 gene," Santoro said.
"Without the birc2 gene, haemorrhage and blood pooling occurred, resulting in vascular regression and cell death," he added.
From the study the researchers come to the conclusion that the findings offers an important insight into the development of the vascular system during embryonic development.
And also suggests a potential target for inhibiting the blood vessels that fuel cancers, diabetic eye complications and atherosclerosis.
"The zebrafish has proven to be an important model for discovering molecules relevant to human disease. We expect this finding will offer important insights into blood vessel formation in humans," Santoro said.
The team discovered the critical role of birc2 and TNF in blood vessel health in the zebrafish embryo, through a series of genomic analyses and biochemical studies.
It was revealed that birc2 was needed for the formation of the tumour necrosis factor receptor complex 1, a group of proteins and peptides, which by initiating signals activate cell survival.
Tumour necrosis factor promotes NF-kB activation. NF-kB is a protein complex transcription factor involved in the transfer of genetic information.
In further tests, it was proved that there was an existence of a genetic link between the birc2/NF-kB pathway, which was critical for vascular health and endothelial cell survival.
"Studies on vascular development are important so that we can better understand the molecular basis of how endothelial cell-related pathologies such as cancer, diabetic eye complications, known as retinopathies, atherosclerosis and system lupus develop," Santoro said.
"It can also help us design new therapeutic strategies for these diseases," he said.
The study is published in Nature Genetics.