Recent identification of TMEM184A as a heparin receptor in vascular cells provides an opportunity to investigate further the mechanism(s) by which the heparin receptor works in vivo. Saturating the heparin receptor decreases vascular smooth muscle cell proliferation and decreases inflammatory responses and angiogenesis in endothelial cells, while decreasing the receptor expression also decreases angiogenesis. The current proposal is designed to expand our knowledge about the heparin receptor and its function in both vascular smooth muscle cells and endothelial cells using a combination of cell culture assays, assays of developmental and regenerative angiogenesis in zebrafish, and employing a null mutant for the heparin receptor currently being developed. Specifically, we will test the hypothesis that the heparin receptor modulates growth factor and adhesion signaling in vascular smooth muscle cells through eNOS activation, examine the hypothesis that mechanotransduction through the endothelial flow mechanosensing complex involves TMEM184A, and test the hypothesis that the heparin receptor collaborates in signaling through the VEGFR2 pathway. Together these studies will provide data to confirm the mechanism(s) by which the heparin receptor is functioning and should yield clues to designing treatments for various vascular diseases that take advance of this modulatory system.

Public Health Relevance

Deaths from cardiovascular disease, complications of angiogenesis, and spending on treatments for individuals suffering from these diseases are major factors in the costs of health care. The drug heparin has been suggested as a treatment that could decrease progression of the disease, but we have a limited understanding of how heparin might work to help slow disease progress. Our recent studies have begun to identify mechanisms and find that the same mechanisms appear to modulate angiogenesis, and the proposed research is designed to increase our understanding of how the drug heparin works at the molecular level to decrease inflammation in blood vessels, and modulate angiogenesis, and should therefore facilitate development of new treatment strategies for vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15HL054269-07
Application #
9590727
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sarkar, Rita
Project Start
2018-08-01
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2021-07-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Lehigh University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
808264444
City
Bethlehem
State
PA
Country
United States
Zip Code
18015
Farwell, Sara Lynn N; Reylander, Kimberly G; Iovine, M Kathryn et al. (2017) Novel Heparin Receptor Transmembrane Protein 184a Regulates Angiogenesis in the Adult Zebrafish Caudal Fin. Front Physiol 8:671
Farwell, Sara Lynn N; Slee, Joshua B; Li, Yaqiu et al. (2017) Using a GFP-tagged TMEM184A Construct for Confirmation of Heparin Receptor Identity. J Vis Exp :
Pugh, Raymond J; Slee, Joshua B; Farwell, Sara Lynn N et al. (2016) Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin. J Biol Chem 291:5326-41
Farwell, Sara Lynn N; Kanyi, Daniela; Hamel, Marianne et al. (2016) Heparin Decreases in Tumor Necrosis Factor ? (TNF?)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1. J Biol Chem 291:5342-54
Gilotti, Albert C; Nimlamool, Wutigri; Pugh, Raymond et al. (2014) Heparin responses in vascular smooth muscle cells involve cGMP-dependent protein kinase (PKG). J Cell Physiol 229:2142-52
Slee, Joshua B; Lowe-Krentz, Linda J (2013) Actin realignment and cofilin regulation are essential for barrier integrity during shear stress. J Cell Biochem 114:782-95
Mengistu, Meron; Brotzman, Hannah; Ghadiali, Samir et al. (2011) Fluid shear stress-induced JNK activity leads to actin remodeling for cell alignment. J Cell Physiol 226:110-21
Blaukovitch, Cheryl Isleib; Pugh, Raymond; Gilotti, Albert C et al. (2010) Heparin treatment of vascular smooth muscle cells results in the synthesis of the dual-specificity phosphatase MKP-1. J Cell Biochem 110:382-91
Hamel, Marianne; Kanyi, Daniela; Cipolle, Mark D et al. (2006) Active stress kinases in proliferating endothelial cells associated with cytoskeletal structures. Endothelium 13:157-70
Savage, J M; Gilotti, A C; Granzow, C A et al. (2001) Antibodies against a putative heparin receptor slow cell proliferation and decrease MAPK activation in vascular smooth muscle cells. J Cell Physiol 187:283-93