Novel Pathway Regulating Angiogenesis: May Fight Retinal Disease, Cancers

ScienceDaily (May 31, 2011) — Scientists have identified in the journal Nature a new molecular pathway used to suppress blood vessel branching in the developing retina -- a finding with potential therapeutic value for fighting diseases of the retina and a variety of cancers.

Branching Retinal Blood Vessels: The top images show (at left) deep layer branching blood vessel formation in the retina of a normal wild-type mouse and (at right) excessive branching in the retina of a mutant mouse unable to produce regulatory Wnt proteins in myeloid cells. The below images show (at left) normal formation of superficial (green) and deep (red) retinal vessels and (at right) excessive formation. The images are from a Cincinnati Children's study published in Nature that researchers say has possible therapeutic implications for diseases of the retina and cancer. 

Researchers report that myeloid cells, blood cells involved in the immune system, use this molecular pathway to guide blood vessel patterning in the retina. Furthermore, in the same study researchers were able to reverse this pathway to accelerate the growth of branching vessels, which could be important to developing new methods for repairing damaged tissues.

"We show in the setting of retina that myeloid cells use this pathway to direct vascular traffic," explained Richard Lang Ph.D., senior investigator on the study and director of the Visual Systems Group in the Division of Ophthalmology at Cincinnati Children's Hospital Medical Center. "We think modulation of this pathway might become a promising therapeutic option.''

The study, to be published online May 29, demonstrates how retinal myeloid cells regulate blood vessel branching in the still-developing retinas of postnatal mice by using the Wnt protein signaling network. The Wnt pathway is known for its role in embryonic and early development as well as in cancer. Although myeloid cells play an important part in the immune system, these cells are also found in many different tumor types and promote tumor progression.

Through a series of experiments in cell cultures and mouse models, researchers determined the new pathway works by myeloid cells utilizing the Wnt pathway to regulate expression of a gene known as Flt1. Flt1 encodes a protein called vascular endothelial growth factor receptor-1 (VEGFR1), which suppresses vascular growth by binding vascular endothelial growth factor (VEGF). The expression of Flt1 can be adjusted so that when ramped up it inhibits VEGF and vascular branching, or when turned down it allows VEGF to increase branching.

Dr. Lang said the Wnt-Flt1 response is a new pathway for regulating VEGF-stimulated angiogenesis (blood vessel formation). This presents a number of new research opportunities to test its influence on retinal diseases that are often associated with abnormal blood vessel development and in tumor formation, he added.

The current study's first author, James (Tony) Stefater, a member of Dr. Lang's laboratory, is an M.D.-Ph.D. graduate student at the University of Cincinnati College of Medicine. Lang, Stefater and their colleagues are already conducting new experiments to see how the pathway influences molecular reactions in retinal disease and in cancer. The cancer studies are being done in collaboration with Jeff Pollard, Ph.D., a cancer cell biologist at the Albert Einstein College of Medicine and co-author on the current study.

The study was supported by funding from the National Eye Institute of the National Institutes of Health, the Howard Hughes Medicine Institute, and included collaborators from those institutions as well as the London Research Institute (Vascular Biology Laboratory) in the United Kingdom and the Center for Skeletal Disease Research, Grand Rapids, Mich.