Robert Friesel, PhD

Faculty Scientist III


BS: Biology, Guilford College
PhD: Biochemistry & Molecular Biology, George Washington University School of Medicine
Postdoctoral Training: NICHD, National Institutes of Health (NIH), Bethesda, MD

Friesel Lab

Understanding signaling pathways that are involved in vascular stability, and how dysfunction of these pathways contributes to vascular diseases such as atherosclerosis, or narrowing of the arteries.

Vascular Homeostasis and Disease

The interests of our laboratory are centered on signaling pathways that are involved in vascular homeostasis, and how dysfunction of these pathways contributes to vascular diseases such as atherosclerosis. Vascular smooth muscle cells (VSMC) of the vessel wall provide overall structure to the vessel and regulate vascular tone in response to external stimuli. Under homeostatic conditions, VSMC exist in a quiescent and contractile state, called the contractile phenotype. Conditions such as vascular injury and vascular inflammation result in VSMC switching from the contractile phenotype to one in which VSMC lose expression of contractile proteins smooth muscle myosin heavy chain (SM-MHC/ MYH11) and begin to proliferate and migrate, a state called the synthetic phenotype. VSMC phenotypic switching is regulated in part by growth factors that activate receptor tyrosine kinases. Although the stimuli are diverse, two key nodes of signal propagation are the phosphatidylinositol-3 kinase (PI3K/AKT) and mitogen-activated protein kinase (MAPK/ERK) pathways. In general, MAPK/ERK activation stimulates VSMC proliferation, migration and inhibits the VSMC contractile phenotype. PI3K/Akt signal promotes VSMC proliferation and, paradoxically, differentiation. The net effect of these signaling pathways on VSMC phenotype likely depends on the strength and the ratio between PI3K/Akt and MAPK/ERK signaling. However, the mechanisms behind this regulation are not fully understood. The Sprouty (Spry) genes were identified as feedback regulators of tyrosine kinase receptor (RTK) signaling pathways. Sprys are reported to affect various components of RTK pathways, and these differences are likely to be receptor or cell type specific. Our recent data indicate that Spry1 is necessary for maintaining the differentiated state of VSMC in vitro whereas Spry4 plays a role in regulating VSMC proliferation. We are currently using mice with gain and loss of function mutations in Spry1 to determine its role in the development of atherosclerosis. Our current investigations show that global deletion of Spry1 in mice results in increased atherosclerosis when Spry1 mice are fed a high-fat Western diet (Fig. 1).

Figure 1. Loss of Spry1 increases hypercholesterolemia-induced atherosclerosis. A) Representative en face Sudan-IV-stained whole aortas show more atherosclerotic lesions in Spry1-/- mice compared to those in Spry1+/+ mice. B) Representative oil red O stained aortic sinus sections show larger atherosclerotic lesions in Spry1-/- mice compared to those in Spry1+/+ mice. Quantification of atherosclerotic plaque area from aortae (C) or aortic roots (D). E) Representative immunostaining shows more F4/80 positive staining of macrophages in lesions of Spry1-/- mice aortic sinuses compared to Spry1+/+ mice. F) Representative images of whole hearts show cardiac hypertrophy and coronary artery atherosclerosis in Spry1-/- mice (indicated by arrows and dash line). G) Representative oil red O stained heart sections show coronary artery atherosclerotic lesions in Spry1-/- mice but not Spry1+/+ mice. Note: *: p<0.05.

Shivangi Pande, MSc

Graduate Student

Research Interests: My research is focused on determining the role of Sef, a negative regulator of the FGF signaling pathway, in the context of vascular inflammation and development of atherosclerosis.

Xuehui Yang, PhD

Staff Scientist

Research Interests: The goal of my research is to define the roles of Sprys and Sef in the pathology of cardiovascular, bone and breast diseases, and apply our understanding of basic mechanisms to clinical diseases.  Learn more about Dr. Yang’s research.

A complete list of publications can be found on My NCBI

Yang, X., Pande, S., Scott, C., Friesel, R.  Macrophage colony-stimulating factor pretreatment of bone marrow progenitor cells regulates osteoclast differentiation based upon the stage of myeloid development. J.Cell.Biochem. 120:12450-12460, 2019 PMCID:PMC6570541

Yang, X., Gong, Y., He, Q., Licht, J.D., Liaw, L., Friesel, R.E. Loss of Spry1 attenuates vascular smooth muscle proliferation by impairing mitogen-mediated changes in cell cycle regulatory circuits. J. Cell. Biochem. 119:3267-3279, 2018 PMCID: PMC5826877

He, Q., Gower, L., Gong, Y., Yang, X., Friesel, R.E. Sef regulates epithelial-mesenchymal transition in breast cancer cells.  J. Cell. Biochem. 117:2346-2356, 2016. PMCID: PMC5382796

Jing, H., Liaw, L., Friesel, R., Vary, C., Hua, S., Yang, X.  Suppression of Spry4 enhances cancer stem cell properties of human MDA-MB-231 breast carcinoma cells. Cancer Cell International, 2016, Mar 11;16:19. PMCID: PMC4787021

Caron, J.M., Ames, J.J., Contois, L., Liebes, L., Friesel, R., Muggia, F., Vary C., Oxburgh, Brooks, P.C. Inhibition of ovarian tumor growth by targeting the HU177 cryptic collagen epitope. Am. J. Pathol. 186:1649-1661, 2016. PMCID: PMC4901133

Ames, J.J., Caron, J., Contois, L., Tweedie, E., Friesel, R., Vary, C.P., Brooks, P.C. Identification of an endogenously generated cryptic collagen epitope (XL313) that selectively regulates angiogenesis by an integrin-YAP-dependent mechano-transduction pathway.  J. Biol. Chem., 291:2731-2750, 2016. PMCID: PMC4742740

Muthukrishnan, S.D., Yang, X., Friesel, R., Oxburgh, L.  Concurrent BMP7 and FGF9 signaling governs AP-1 function to promote self-renewal of nephron progenitor cells. Nat. Commun., 6:10027, 2015.  PMCID: PMC4686668

Contois, L.W., Akalu, A., Caron, J.M., Tweedie, E., Cretu, A., Henderson, T., Liaw, L., Friesel, R., Vary, C, Brooks, P.C.  Inhibtion of tumor associated avb3 integrin regulates the angiogenic switch by enhancing the expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo. Angiogenesis, 18(1):31-46, 2015.  PMCID: PMC4281512

Yang, X., Liaw, L., Prudovsky, I., Brooks, P.C., Vary, C.P., Oxburgh, L., Friesel, R. Fibroblast Growth Factor Signaling in the Vasculature. Current Atherosclerosis Reports, 17:509, 2015.

He, Q., Yang, X., Gong, Y., Kovalenko, D., Canalis, E., Rosen, C.J., and Friesel, R.E. Deficiency of Sef in mice is associated with increased postnatal cortical bone mass by regulating Runx2 activity. J. Bone Miner. Res., 29(5):1472-1431, 2014. PMCID: PMC3984377

Yang, X., Gong, Y., Tang, Y., Li, H., He, Q., Gower, L., Liaw, L., and Friesel, R.E. Spry1 and Spry4 differentially regulate human aortic smooth muscle cell phenotype via Akt/FoxO/myocardin signaling. PLoS One, 8(3):e58746, 2013. PMCID: PMC3598808

Gong, Y., Yang, X., He, Q., Prudovsky, I., Vary, C.P.H., Brooks, P.C., and Friesel, R.E. Sprouty4 regulates endothelial cell adhesion and migration by regulating c-Src activation and integrin b3 stability. Angiogenesis, 16:861-875, 2013. PMCID: PMC3790316

Contois, L.W., Nugent, D.P., Caron, J.M., Cretu, A., Tweedie, E., Akalu, A., Liebes, L., Friesel, R., Rosen, C., Vary, C., and Brooks, P.C. Insulin-like growth factor binding protein-4 (IGFBP-4) differentially inhibits growth factor induced angiogenesis. J Biol Chem., 287(3):1779-1789, 2012. PMCID: PMC3265860

Brown, A., Adams, D., de Caestecker, M., Yang, X., Friesel, R., and Oxburgh, L. FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development. Development, 138:5099-5112, 2011. PMCID: PMC3210493

Tang, Y., Yang, X., Friesel, R.E., Vary, C.P.H., Liaw, L. Mechanisms of TGFb induced differentiation in human vascular smooth muscle cells. J Vascular Research, 48(6):485-494, 2011. PMCID: PMC3169366

Yang, X., Gong, Y., and Friesel, R. Spry1 is expressed in hemangioblasts and negatively regulates primitive hematopoiesis and endothelial cell function. PLoS One, 6(4):e18374, 2011. PMCID: PMC3069969

Urs, S., Venkatesh, D., Tang, Y., Henderson, T., Yang, X., Friesel, R.E., Rosen, C.J., and Liaw, L. Sprouty1 is a critical regulatory switch of mesenchymal stem cell lineage allocation. FASEB J., 24:3264-3273, 2010. PMCID: PMC2923355

Yang, X., Harkins, L.K., Zubanova, O., Harrington, A., Kovalenko, D., Nadeau, R.J., Chen, P.Y., Toher, J.L., Lindner, V., Liaw, L., and Friesel, R. Overexpression of Spry1 in Chondrocytes Causes Attenuated FGFR Ubiquitination and Sustained ERK Activation Resulting in Chondrodysplasia. Developmental Biology, 321:64-78, 2008. PMCID: PMC2548288

Academic Affiliations

  • Member, Graduate Faculty, Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine
  • Professor, Department of Medicine, Tufts University School of Medicine, Boston, MA
  • Faculty Member, Molecular, Cell, and Developmental Biology Graduate Program, Tufts University Graduate School of Biomedical Sciences, Boston, MA

Professional Activities

  • Member, American Heart Association
  • Member, American Association for the Advancement of Science
  • Member, External Advisory Committee, Pediatric COBRE, Sanford Research Institute, Sioux Falls, South Dakota
  • Reviewer, American Heart Association
  • Reviewer, COBRE Phase I Special Emphasis Panel, NIGMS, National Institutes of Health
  • Member, editorial board, Cells