The often forgotten lymphatic circulatory system may be intimately involved in vascular disorders, according to a study by researchers from the Medical School and University of Michigan. Their research was reported recently in the Proceedings of the National Academy of Sciences.
Because the lymphatic vessels develop from the venous system, researchers reasoned it might be expected to play a role in vascular disorders. Using genetic analysis and a new lymphatic imaging technique, the team showed that the lymphatics are involved in a rare vascular disorder, Parkes-Weber syndrome, in humans and confirmed the finding in mice. The finding could enable better diagnosis and treatment of more common vascular problems.
The network of lymphatic vessels forms a unidirectional circulation system, which returns cellular materials, absorbed fat, immune cells and, most important, excess fluid that is normally “leaked” from small blood vessels, back to the blood circulation. When the lymphatics are not functioning, malnutrition, infection and severe edema can ultimately result, further complicating diagnosis and treatment of vascular disorders.
In their study conducted in the Department of Diagnostic and Interventional Imaging, the team imaged the lymphatics in a patient with a suspected RASA1 mutation that is known to be linked to Parkes-Weber syndrome. This syndrome presents with capillary malformations and arteriovenous fistulas that are associated with abnormal bleeding and heart failure.
Imaging techniques included near-infrared fluorescence lymphatic imaging (NIRFLI) developed using military night-vision goggle technology.
Drs. John Rasmussen, Melissa Aldrich, and Sunkuk Kwon, co-authors and assistant professors at the Medical School’s Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, imaged the lymphatics using the NIRFLI camera system. The patient was injected with a tiny amount of fluorescent dye that could be imaged through the skin and observed traveling in lymphatic vessels. This allowed researchers to track the flow of lymph fluid through the system, revealing an abnormal network of lymphatic vessels in the patient. Using state-of-the-art whole exome sequencing techniques and bioinformatics techniques, Dr. Manuel Gonzalez-Garay, co-author and assistant professor in the Center for Molecular Imaging, then singled out RASA1 as the only potential causative gene of the disorder in the human research subject.
Researchers confirmed the human subject findings in a mouse model developed at the University of Michigan by co-authors, Drs. Philip Lapinski and Philip King. The mouse model not only had a similar RASA1 mutation to the human subject but a similarly abnormal lymphatic system as imaged by NIRFLI.
“This study is a game changer,” said Dr. Eva Sevick-Muraca, senior author and holder of the Nancy and Rich Kinder Distinguished Chair in Cardiovascular Disease Research. “This is a rare case in which we were able to image lymphatic abnormalities in both a patient and a mouse model that harbored similar mutations known only to be associated with vascular malformations. The striking results underscore the potential role of the lymphatics in vascular disorders.”
Besides their discoveries that directly relate lymphatic and vascular abnormalities, the team’s genetic discovery could be used to identify future pharmacologic strategies to alleviate more common lymphatic disorders. Currently, there is no cure for diseases and chronic conditions associated with the lymphatic system. Rare, inheritable lymphatic disorders are thought to be caused by gene mutations, many of which are unknown. More common lymphatic disorders arise following trauma or cancer treatment, including surgery and radiation. To date, there are no approved drugs to manage both these rare and more common lymphatic disorders.
Co-authors on the study included clinical researchers Drs. Patricia Burrows, Renie Guilliod, Erik Maus, and Caroline Fife.
The study, which is titled “Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man,” received support from National Institutes of Health grants (R01 HL092923, R01 CA128919 and R01 HL096498) and American Heart Association grant (11POST7580023).
-Rob Cahill, Office of Advancement, Media Relations