Heparin Effects in the vasculature

Heparin is best known as an anticoagulant, but heparin and related carbohydrate chains referred to as heparan sulfates do much more than alter blood clotting.  A major focus of research in the laboratory is aimed at improved understanding of the mechanisms by which heparin alters the physiology of endothelial and vascular smooth muscle cells.  Publications from the laboratory have identified aspects of heparin induced signaling including the involvement of cGMP-dependent protein kinase and induction of MKP-1/DUSP1, a phosphatase that inactivates MAPK enzymes.  We continue to study signaling events in vascular cells that occur in response to heparin treatment.

Heparin Receptor

Starting with monoclonal antibodies we developed that mimic heparin effects on vascular cells, we have identified a candidate heparin receptor and are now carrying out studies to determine the extent to which this protein is involved in vascular cell responses to heparin. 

The newest research area in the laboratory is in collaboration with the Iovine laboratory to investigate the involvement of the heparin receptor activated by our monoclonal antibodies in the vasculature of zebrafish.

Field, C., Perez, A., Samet, T., Ricles, V., Iovine, M. K., and Lowe-Krentz, L.. 02 September 2022. Involvement of transmembrane protein 184a during angiogenesis in zebrafish embryos. Front. Physiolo.

Dong, C., Choi, Y.K., Lee, J, Zhang, F, Honerkamp-Smith, A, Widmalm, G., Lowe-Krentz, L., Im, W. 2021. Structure, Dynamics, and Interactions of GPI-Anchored Human Glypican-1 with Heparan Sulfates in a Membrane. Glycobiology. 31:593-602 .

Li, Y, Talotta-Altenburg, LM, Silimperi, K, Ciabattoni, G and Lowe-Krentz, L.J. 2020. Endothelial nitrous oxide synthase activation is required for heparin receptor effects on vascular smooth muscle cells. Am J. Physiol. Cell Phys. 318: c463-C475. Doi10.1152/ajpcell.00284.2018

Farwell, S.L.N., Reylander, K.G., Iovine, M.K. and Lowe-Krentz, L.J. 2017. Novel Heparin Receptor Transmembrane Protein 184a Regulates Angiogenesis in the Adult Zebrafish Caudal Fin. Front. Physiol., 07 Sept 2017 doi.org/10.3389/fphys.2017.00671

Farwell SL, Slee JB, Li Y, Lowe-Krentz LJ. Using a GFP-tagged TMEM184A Construct for Confirmation of Heparin Receptor Identity. J Vis Exp. 2017 Feb 17;(120). doi: 10.3791/55053.

Thomas, A., Ou-Yang, H.D., Lowe-Krentz, L., Muzykantov, V.R. and Liu, Y. 2016. Biomimetic channel modeling local vascular dynamics of pro-inflammatory endothelial changes.  Biomicrofluidics.  10, 014101 (January, 2016) DOI: 10.1063/1.4936672

Pugh, R., Slee, J.B., Farwell, S.L.N., Li, Y., Barthol, T., Patton, W.A. and Lowe-Krentz, L.J. 2016.  Transmembrane protein 184A is a receptor required for vascular smooth muscle cell responses to heparin.  J. Biol. Chem. 2016 Jan 14pii: jbc.M115.681122.

Farwell, S.L.N., Kanyi, D., Hamel, M., Slee, J.B., Miller, E.A., Cipolle, M.D., Lowe-Krentz, L.J.  2016. Heparin decreases in TNFα-induced endothelial stress responses require transmembrane protein 184A and induction of dual specificity phosphatase-1. J. Biol. Chem. 2016 Jan 14 pii: jbc.M115.681288.

Gilotti, AC, Nimlamool, W, Pugh, R, Slee JB, Barthol TC, Miller EA, and Lowe-Krentz, LJ. 2014.  Heparin responses in vascular smooth muscle cells involve cGMP dependent protein kinase. J Cell. Physiol. 229: 2142-2152. 

Slee, J.B. and Lowe-Krentz, L.J. 2013. Actin realignment and cofilin regulation are essential for barrier integrity during shear stress. J. Cellular Biochemistry. 114:782-795. Published on-line in Oct 2012 as: DOI: 10.1002/jcb.24416.

Mengistu, M., Slee, J.B., and Lowe-Krentz, L.J.  2012.  Ch V.  Stressed out and actin up:  stress-activated protein kinase regulation of actin remodeling directs endothelial cell morphology and migration.  In:  Actin: Structure, Functions and Disease.  Eds. VA Consuelas, et al., Hauppauge, NY: Nova Sciences Publishers, Inc.  ISBN: 978-1-62100-191-1. Pp 177-205.

Slee, J.B., Pugh, R., and Lowe-Krentz, L.J: Ch III. Beyond anticoagulation – Roles for heparin in the vasculature. In: Heparin: properties, uses and side effects. Eds. DE Piyathilake and Rh Liang, (2012) Nova Sciences Publishers, Inc. Hauppauge, NY ISBN: 978-1-62100-431-8. Pp 59-81.

Aranibar, N., Vassallo, J.D., Rathmacher, J., Stryker, S., Robertson, D., Reily, M., Lowe-Krentz, L., Lois Lehman-McKeeman: Identification of 1- and 3-Methylhistidine as Biomarkers of Skeletal Muscle Toxicity by NMR-based Metabolic Profiling. (2011) Analytical Biochemistry 410:84-91.

Mengistu, M., Brotzman, H., Ghadiali, S., and Lowe-Krentz, L.J.: Fluid shear stress-induced JNK activity leads to actin remodeling for cell alignment. (2011) J. Cellular Physiology, 226(1):110-21

Blaukovitch, C.I., Pugh, R., Gilotti, A.C., Kanyi, D., and Lowe-Krentz, L.J.: Heparin treatment of vascular smooth muscle cells results in the synthesis of the dual-specificity phosphatase, MKP-1. (2010) J. Cellular Biochemistry 110: 382-391.

Vassallo, J.D., Janovitz, E.B., Wescott, D.M., Chadwick, C., Lowe-Krentz, L.J., and Lehman-McKeeman, L.D.: Biomarkers of drug-induced skeletal muscle injury in the rat: troponin I and myoglobin. (2009) Toxological Sciences 111: 402-412.

Hamel, M, Kanyi, D.M., Cipolle, M.D., and Lowe-Krentz, L.J.: Active Stress Kinases in Proliferating Endothelial Cells Associated with Cytoskeletal Structures. (2006) Endothelium. 13:157-170.

Savage, J., Gilotti, A.C., Granzow, C., Molina, F., Lowe-Krentz, L.J.: Antibodies against a heparin receptor slow cell proliferation and decrease MAPK activation in vascular smooth muscle cells. (2001) J. Cell Physiol. 187:283-293.

Dougherty, C.S. and Lowe-Krentz, L.J.: Heparin increases protein S levels in cultured endothelial cells by causing a block in degradation. (1998) J. Vascular Res. 35, 437-448.

Patton, W.A.,II, Granzo w, C.A., Getts, L.A., Thomas, S.C., Zotter, L.M., Gunzel, K.A., and Lowe-Krentz, L.J., Identification of a heparin binding protein using monoclonal antibodies that block heparin binding to porcine aortic endothelial cells. (1995) Biochemical. J. 311, 461-469.

Graduate Students

Current

Leanna Altenburg

Ph.D. Alumni

Yaqiu Li, Ph.D., '19

Sara Lynn Farwell, Ph.D., '18

Joshua Slee, Ph.D., '13
Wutigri Nimlamool, Ph.D., '13
Jeffrey Vassallo, Ph.D., '12
Raymond Pugh, Ph.D., '10
Meron Mengistu, Ph.D., '08
Daniella Kanyi, Ph.D., '07
Susan Spits, Ph.D., '02
Albert Gilotti, Ph.D., '01
Marianne Hamel, Ph.D., '01
Catherine Granzow, Ph.D., '97
Cristy Stanley Dougherty, Ph.D., '96
Walter A. Patton, Ph.D., '94