JUL 04, 2020 2:49 PM PDT

Discovering a New Signal Junction Controlling Pulmonary Arterial Hypertension

WRITTEN BY: Jasper Cantrell

Pulmonary Arterial Hypertension (PAH) is a progressive and fatal disease characterized by the muscularization of blood cells that otherwise have no muscle. This generally leads to an increase in something called pulmonary vascular resistance (PVR). Essentially making it harder for blood to circulate throughout the body.

Growth factors are small proteins responsible for inducing many pathways, including pathways involved in the onset of PAH. Midkine is one such growth factor that has been linked to cardiovascular problems such as heart failure and the muscularization of blood vessels. It is also linked to the upregulation of another growth factor, epidermal growth factor (EGFR), a key player in the muscularization of blood vessels.  

The receptor that brings both growth factors together is called nucleolin. Nucleolin is a cell receptor controlled by hypoxia, i.e., oxygen deprivation. A team from the School of Medicine at Yamagata University in Japan hypothesized that hypoxia could induce a signal cascade from the upregulation of nucleolin to the binding of midkine, stimulating EGFR signaling. All this would result in the muscularization of blood vessels and cause PAH.

The muscularization itself is conducted by what are called pulmonary arterial smooth muscle cells (PASMCs). These cells migrate to blood vessels after being activated by outside signaling. In mouse models, when midkine blood levels were high or hypoxic conditions occurred, there was a clear increase in the migration of PASMCs to blood vessels. There was also a clear increase in EGFR signaling.  

The team used nucleolin gene and protein inhibitors to examine the relationship between midkine, nucleolin, and EGFR. Inhibiting nucleolin disrupted EGFR’s activation by preventing midkine from binding. Taking this observation, they used PAH prone mice to confirm the effects of nucleolin inhibitors. Indeed, upon application of the inhibitor, the muscularization of the blood vessels decreased compared to controls.

To sum it all up, under hypoxic conditions, the cell would produce nucleolin at the cell surface. Midkine would then bind to it and activate the EGFR signaling pathway. The EGFR pathway would then go on to cause the muscularization of blood vessels by migrating PASMCs to the blood vessels.

This is quite an interesting discovery. This study not only identified a connection between midkine, nucleolin, and EGFR, but it showed it was also a possible drug target. By inhibiting the midkine interaction with nucleolin, it could prevent EGFR signaling. This would effectively halt the muscularization process and prevent PAH. While further research is needed, the idea of a simple drug that could treat or prevent PAH is quite a find.

The group concludes, “The results of our study demonstrated that midkine plays an important role in the pathogenesis of PAH, and midkine-nucleolin-EGFR axis may represent a novel therapeutic target for PAH.”

Sources: Nature Scientific Reports, Atrium Collabarative

About the Author
  • Hey everyone! My name is Jasper and, considering I am pretty new here to Labroots, I figured I would introduce myself. I received my bachelor’s from the University of California at Riverside back in 2016. I started off my career a few years ago with a job at a University over in New York, before moving over into the industry. I'm happy to be writing content for Labroots, and I hope you enjoy it!
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