Developmental biology - Diabetes|
Misaligned Blood Vessel Cells Leak In Diabetes
An enzyme in diabetics causes aligned blood vessel cells to misalign, allowing veins and arteries to leak three times more blood than normal...
An enzyme activated in diabetics has been found to cause previously aligned cells in a blood vessel to reverse their orientation, creating misalignments that allow veins and arteries to leak three times more blood proteins than normally constructed blood vessels. Controlling the enzyme could ease symptoms of swelling, nerve pain, localized low blood pressure, and risk of infection in diabetes, other diseases that cause blood vessels to leak, and smoking.
The finding, published in Science Advances, stems from a closer examination of the chirality, or "handedness," of cells. Chirality is a property of asymmetry found at all scales of life, from the level of molecules to whole organisms. Like left and right hands, cells that display chirality are mirror images of one another. This is the first study to move beyond the effects of cell chirality on embryonic development, and examine its effects on physiological processes.
"This research tells us that chirality can change in your lifetime after birth, which is surprising. But if we see that disease can reverse chirality, we can also envision targeted therapies to block that process."
Leo Wan PhD, Associate Professor of Biomedical Engineering, Member of the Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, and lead author of the research.
The endothelial cells that line the interior of a blood vessel commonly share a right-hand orientation, fitting neatly together to form a semi-permeable barrier that tightly controls the passage of proteins and cells from the bloodstream into surrounding tissue. But new research shows that even low levels of the protein kinase C (PKC) - activated in diseases like diabetes - can cause some cells in blood vessels to reverse chirality, flipping to a left-hand orientation creating gaps between right- and left-hand cells that increase permeability threefold.
Understanding this process could lead to development of a therapy to block alterations of cell chirality inside blood vessels, a targeted approach Wan anticipates as fairly easy to achieve.
The domestication of transposable elements has repeatedly occurred during evolution and domesticated transposases have often been implicated in programmed genome rearrangements, as remarkably illustrated in ciliates. In Paramecium, PiggyMac (Pgm), a domesticated PiggyBac transposase, carries out developmentally programmed DNA elimination, including the precise excision of tens of thousands of gene-interrupting germline Internal Eliminated Sequences (IESs). Here, we report the discovery of five groups of distant Pgm-like proteins (PgmLs), all able to interact with Pgm and essential for its nuclear localization and IES excision genome-wide. Unlike Pgm, PgmLs lack a conserved catalytic site, suggesting that they rather have an architectural function within a multi-component excision complex embedding Pgm. PgmL depletion can increase erroneous targeting of residual Pgm-mediated DNA cleavage, indicating that PgmLs contribute to accurately position the complex on IES ends. DNA rearrangements in Paramecium constitute a rare example of a biological process jointly managed by six distinct domesticated transposases.
Julien Bischerour, Simran Bhullar, Cyril Denby Wilkes, Vinciane Régnier, Nathalie Mathy, Emeline Dubois, Aditi Singh, Estienne Swart, Olivier Arnaiz, Linda Sperling, Mariusz Nowacki and Mireille Bétermier.
The research was supported with a combination of funding from the National Institutes of Health, National Science Foundation, American Heart Association, March of Dimes, and Pew Charitable Trusts. The authors of "Cell Chirality Regulates Intercellular Junctions and Endothelial Permeability" also include Jie Fan, Poulomi Ray, Gurleen Kaur of Rensselaer Polytechnic Institute, and Yaowei Lu and John J. Schwarz of Albany Medical College.
This research is part of a larger focus on translational medicine in diseases, including diabetes, at the Center for Biotechnology and Interdisciplinary Studies, and is an example of the collaborative work that is central to The New Polytechnic, the driving model for teaching, learning, and research at Rensselaer.
About Rensselaer Polytechnic Institute
Rensselaer Polytechnic Institute, founded in 1824, is America's first technological research university. For nearly 200 years, Rensselaer has been defining the scientific and technological advances of our world. Rensselaer faculty and alumni represent 86 members of the National Academy of Engineering, 18 members of the National Academy of Sciences, 26 members of the American Academy of Arts and Sciences, 8 members of the National Academy of Medicine, 8 members of the National Academy of Inventors, and 5 members of the National Inventors Hall of Fame, as well as 6 National Medal of Technology winners, 5 National Medal of Science winners, and a Nobel Prize winner in Physics. With 7,000 students and nearly 100,000 living alumni, Rensselaer is addressing the global challenges facing the 21st century--to change lives, to advance society, and to change the world. To learn more, go to http://www.rpi.edu.
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An enzyme activated in diabetics causes previously aligned cells in a blood vessel to reverse their orientation, creating misalignments that allow veins and arteries to leak three times more blood proteins than normally constructed blood vessels. Image credit: Rensselaer University