Catherine Yang

A Yale-led team of researchers has taken the next step in understanding blood vessel development.

The researchers helped to illuminate the “crosstalk,” or the communication of pathways within a cell, among various processes involved in the formation of blood vessels. The published findings represent a significant advance in the understanding of the genetics associated with vascular maturation.

The team was led by senior author Hyung Chun, professor at the Yale School of Medicine. Chun and his lab collaborated with a multinational group of researchers, including scientists from the Max Planck Institute, the Sookmyung Women’s University, Stanford University and the Massachusetts Institute of Technology. Their results confirmed a connection previously suggested by other studies — that blood flow regulates the expression of CXCR4, a gene important to vascular development. However, they also identified and characterized two new chemical players involved in this process of regulation.

Specifically, the study showed that blood flow patterns directly regulate the expression of the Apelin gene, which in turn controls the expression of the CXCR4 gene through microRNA139-5p, a small RNA molecule. Because certain statin drugs — a class of medications that lower cholesterol levels — are known to influence this microRNA, the discovery will empower researchers to develop new treatments for vascular disease, according to the study. By targeting this microRNA molecule, scientists can manipulate the expression of the CXCR4 gene, which is implicated in diseases as diverse as cancer and atherosclerosis, the thickening of artery walls. The study was published in the journal Nature Communications on April 12.

“We found that maturation of blood vessels in vertebrates require ‘turning on’ or ‘shutting off’ of distinct signaling pathways through a microRNA,” Chun said in a Sunday email to the News. “The crosstalk achieved by this microRNA-based signaling was found to be necessary for normal blood vessel development.”

According to both Chun and co-author Arndt Siekmann, researcher at the Max Planck Institute, the main driving force behind the study was the Chun lab’s previous work on signalling pathways involved in cardiovascular health. In particular, the conclusions the team reached about blood flow and the participation of the Apelin gene in the regulation process were directly prefaced by much of the Chun lab’s work with zebrafish embryos, said Siekmann.

This most recent study relied heavily on knocking out certain genes in order to correlate them with their functions in the vascular system. For this study, mice, not zebrafish, were used as the test organism. The team’s results eventually suggested a rather surprising mechanism, according to Siekmann, because the role of microRNA in the process was unexpected prior to the study.

MicroRNA are small noncoding RNA molecules that work to regulate messenger RNA, which encodes proteins. The small microRNA molecules attach to complimentary strands of mRNA to “silence” the mRNA and ensure that its information is not translated to create proteins. According to the researchers, this silencing is a form of “down” regulation, which is what is seen in the crosstalk between blood flow patterns and the expression of the important CXCR4 gene, which governs many elements of vascular development. By isolating the role of microRNA in this process, the researchers were able to fill in the missing steps in the pathway regulating CXCR4.

According to the study, the practical implications for the researchers’ findings are broad: Many diseases related to the vascular system are associated with the CXCR4 gene.

“We hope that our recent studies on blood vessel development will shed novel insights into the mechanisms that may be playing key roles in disease contexts, such as in cancer and heart disease,” Chun said.

Another avenue for future research suggested by this study is the process of transcription for the involved microRNA molecule, Siekmann said. Transcription is the process in which the DNA of a cell is converted into RNA so that it can be used to create proteins. The transcription factors that regulate the process of transcription are currently not identified nor understood in the case of the microRNA molecule involved in the CXCR4 pathway. Understanding this would allow scientists to more fully explain the pathway connecting the Apelin gene to the expression of microRNA, and for this reason, Siekmann said he believes the next step for research related to this area in vascular development will focus on bringing to light this process of transcription.

According to the Centers for Disease Control, around 610,000 people each year die of heart disease in the United States, accounting for approximately one in four deaths.

Correction, April 28: A previous version of this article misstated the name of the journal the study was published in; in fact, it was Nature Communications.