Gridlock keeps blood flowing, hearts in check

Leigh MacMillan, Ph.D.
Published: August, 2008

Gridlock can be a good thing. If you’re talking about cardiovascular development, that is.

Tao Zhong, Ph.D., peers through a tank of zebrafish.
Photo by Neil Brake
In developing zebrafish embryos, a gene and the protein it encodes (both named Gridlock) play key roles in blood vessel formation and heart growth.

Gridlock got its name from what happens when it’s not working correctly. Blood “traffic” gets snarled in zebrafish with a mutation in the Gridlock gene – the fish fail to develop circulation to the trunk and tail because of a blockage at the base of the aorta.

Tao Zhong, Ph.D., has been tangling with the Gridlock gene since he first isolated it during his postdoctoral fellowship at Harvard Medical School.

Now an assistant professor of Medicine, Pharmacology, and Cell & Developmental Biology at Vanderbilt, Zhong hopes that pursuing the roles of Gridlock and other signaling proteins in heart and blood vessel development will lead to novel strategies for treating human cardiovascular disorders.

In their initial studies of Gridlock, Zhong and colleagues showed that a Gridlock signaling pathway determines whether blood vessel cells will become part of arteries or veins, and that it controls assembly of the aorta.

More recently, Zhong’s team demonstrated that Gridlock works with Gata5, another signaling protein that turns genes on and off, to control heart size in developing zebrafish. Gata5 acts like a car’s accelerator, turning on genes that increase cell size and division, while Gridlock acts like the brakes, keeping growth from getting out of control.

The findings are exciting, Zhong says, because they suggest that tapping into the Gridlock signaling pathway may offer a way to spur adult cardiac cells to divide.

In damaged adult hearts, cardiac cells increase in size in an attempt to provide more pumping power, but they are not able to divide. Eventually, the individual cells become too large to be effective, contributing to dilated cardiomyopathy (enlarged heart) and heart failure.

“We think that if we can inactivate the Gridlock side of the pathway (take off the brakes), that may provide a therapeutic approach to turn on proliferation machinery in adult cardiac myocytes (muscle cells),” Zhong says.

Zhong is also exploring whether variations in the Gridlock gene may be responsible for some human congenital heart diseases, which occur in one in 100 live births and remain the leading cause of death in the first year of life.

The blood vessel blockage in zebrafish with a mutation in Gridlock resembles a human disorder called coarctation (constriction) of the aorta. Recent studies have also linked a Gridlock mutation to a human septal defect – a hole in the dividing wall of the heart.

Zhong is setting up international collaborations to search for Gridlock and other developmental gene mutations in patients with cardiovascular diseases.

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