Heart Diseases; Vascular Diseases; Cardiovascular Abnormalities
Public Health Interests
Cancer; Cardiovascular Disease; Heart Disease; Stroke
Stem Cell Center, Yale: Signal Transduction and Cell Growth
Understanding of the fundamental molecular mechanisms for inflammation may lead to improved therapeutic strategies for treatment of vascular diseases such as atherosclerosis. The vascular cells that primarily respond to inflammatory stimuli are the vascular endothelial cells (EC). The goal in my lab is to dissect the inflammatory signaling pathways in EC involved in vasculature. For over 15 years, my laboratory has been funded through 8 NIH, 3 AHA grants and 2 industry Research Agreements to define the critical molecules mediating inflammatory responses, and their roles in progression of vascular diseases such as atherosclerosis, graft transplant rejection and tumor metastasis. We have been the leader in the field of inflammation/stress signaling.
Since 2008, my lab has expanded our research to vascular development and remodeling. The goal in my lab is to dissect the signaling pathways, establish mouse models and define the fundamental mechanisms involved in vascular development, remodeling and repair related to human diseases such as vascular malformation, ischemia and stroke. In the past 4 years, my lab has extensively employed biochemical, cell biological and mouse genetic approaches to define the critical molecules mediating vascular development, remodeling and repair. These new projects are currently funded by 2 NIH (as PI) and 2 AHA (as a mentor) grants. These projects fit very well to the overall research mission in the Department of Pathology and the Program of Vascular Biology & Therapeutics (VBT).
Extensive Research Description
Research Interests and Approaches: Understanding of the fundamental molecular mechanisms for vasculogenesis, arteriogenesis, angiogenesis and lymphangiogenesis may lead to improved therapeutic strategies for treatment of vascular diseases. The vascular cells that primarily respond to inflammatory stimuli are the vascular endothelial cells (EC). The goal in my lab is to dissect the signaling pathways in EC involved in vascular development, remodeling and disease progression (Fig.1). We have used biochemical, cell biological and mouse genetic approaches to define the critical molecules mediating vascular development, remodeling and vascular disease progression (Fig.2).
1. Inflammation-mediated angiogenesis and lymphangiogenesis (Fig.3). Both angiogenesis and lymphangiogenesis are critical for tissue repair. We have identified the TNFR2-Bmx kinase (bone marrow tyrosine kinase in X chromosome)-VEGFR2/3 signaling pathway involved in EC proliferation, migration and tube formation. We are investigating how TNFR2-Bmx mediates angiogenesis, lymphangiogenesis and vascular tissue repair.
2. Vascular development, endothelial cell progenitors and vascular malformation. In addition to Bmx, we have identified several intracellular molecules (AIP1, CCM3 and Epsin) regulating VEGFR2, a critical tyrosine receptor kinase in vascular development, EC progenitor cell differentiation and vascular remodeling. We have generated conditional knockout mice with a deletion of each gene, and these mice will provide useful tools to define the mechanism underlining human vascular diseases such as cerebral cavernous malformations, retinopathy and tumor metastasis.
3. Stress signaling pathways in EC. We have identified several critical upstream regulators of ASK1 (a member of MAP3K family) and have made several original discoveries in elucidating the mechanisms for ASK1 activation by various stresses (cytokine, oxidative stress, genotoxic stress and ER stress (see Fig.4 from a Recent review article in 2009). We are determining how these mediators are specifically activated in response to stress.
4. Determine the mechanism of tumor progression and metastases. We have identified AIP1, a new member of Ras-GAP family protein (also known as DAB2IP), as a potential tumor suppressor gene. We are employing variety of tumor models to determine the role of AIP1 in tumor growth and metastasis.
- Zhou HJ, Qin L, Zhang H, Tang, W, Ji, W, He Y, Liang, X, Wang Z, Yuan Q, Vortmeyer A, Toomre D, Fuh G, Yan M, Kluger MS, Wu D, Min W* (2016). Endothelial exocytosis of angiopoietin-2 resulting from CCM3-deficiency contributes to cerebral cavernous malformation. Nature Medicine 22(9):1033-42.
- Zou S, Teixeira AM, Yin M, Xiang Y, Xavier-Ferruccio J, Zhang PX, Hwa J, Min W, Krause DS. (2016) Leukaemia-associated Rho guanine nucleotide exchange factor (LARG) plays an agonist specific role in platelet function through RhoA activation. Thromb Haemost. 116(3). 116(3):506-16. Cover story at https://th.schattauer.de/en/contents/archive/issue/2392/manuscript/26004.html
- Shao, L, Zhou HJ, Zhang H, Qin L, Hwa, J, Yun Z, Ji, W, Min W* (2015). SENP1-mediated NEMO deSUMOylation in the adipocyte limits inflammatory responses and type 1 diabetes progression. Nature Communications 6:8917. doi: 10.1038/ncomms9917.
- Ji W, Li Y, He, Y., Yin M., Zhou, HJ., Boggon TJ., Zhang H., Min W.* (2015). AIP1/DAB2IP-mediated signaling in tumor niche suppresses tumor progression and metastasis. Cancer Res 75(17):3492-504.
- Zhang, JQ, Zhou, HJ, Ji, W, Min W.* (2015). AIP1-Mediated Stress Signaling in Atherosclerosis and Arteriosclerosis" Current Atherosclerosis Reports, 17(5):503.
- Huang Q., Zhou HJ, Zhang H, Zhou HJ, Huang Y, Fan P., Yao L., Belardinelli L, Tellides T, Giordano FJ, Budas GR, Min W* (2015). Thioredoxin-2 inhibits mitochondrial ROS generation and ASK1 activity to maintain cardiac function. Circulation 131(12):1082-97.
- Zhou, HJ, Chen, X, Huang, Q., Zhang, H, Wang, Y, Yu, J, Liu, R, Li, Y, Xu, Z, and Min, W.* (2014) AIP1 mediates VEGFR3-dependent angiogenic and lymphangiogenic responses. Arterioscler Thromb Vasc Biol. 34(3):603-15.
- Zhang, Y., Tang, W., Zhang, H., Niu, X., Xu, Y., Zhang, J., Gao, K., Boggon, TJ., Toomre, D., Min, W.*, Wu, D.* Important roles of the CCM3 and STK24 Complex in regulation of Ca2+-stimulated exocytosis. Dev Cell. 27(2):215-26. (*Min is co-corresponding author).
- Qin, L., Huang, Q., Zhang, H., Liu, R., Tellides, G., Min, W*, Yu, L*. (2014). SOCS1 prevents graft arteriosclerosis by preventing endothelial cell function. J Amer Coll of Cardiol. 63(1):21-9 (*Min is contacting senior author). Also see commentary in this issue by Weger, RA Immune regulators regulated to prevent transplant reactions. This work was the winner for JACC Parmley Award in 2013.
- Kallen, AN., Xu, J., Qiao, C., Martinet, C., Lu, L., Ma, J., Zhou, XB., Yan, L., Liu, C., Yi, JS., Zhang, H., Min, W., Gregory, RI., Bennett, AM., Gabory, A., Dandolo, L., Huang, Y. (2013). H19 IncRNA acts as a natural sponge for let-7 miRNAs. Mol Cell. 52(1):101-12.
- Al-Lamki RS, Lu W, Wang J, Yang J, Sargeant TJ, Wells R, Suo C, Wright P, Goddard M, Huang Q, Lebastchi AH, Tellides G, Huang Y, Min W, Pober JS, Bradley JR (2013). TNF, Acting through Inducibly Expressed TNFR2, Drives Activation and Cell Cycle Entry of c-kit+ Cardiac Stem Cells in Ischemic Heart Disease. Stem Cells. (Epub ahead of print May 27, 2013).
- Wu, K., Liu, J., Tseng, SF, Gore, C., Sharifi, N., Fazli, L., Gleave, M., Kapur, P., Xiao, G., Sun, X, Oz, OK., Min, W., Alexandrakis, G., Yang, CR, Hsieh, CL, Wu, HC, He, D., Xie, D., Hsieh, JT. (2013) The role of DAB2IP in androgen receptor activation during prostate cancer progression. Oncogene. Online publication, April 22, 2013.
- Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W,, McLendon RE, Rich JN, Bao S. (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153(1):139-52.
- Huang, Q., Qin, L., Dai, S., Zhang, H., Pasula, S., Zhou, H., Chen, H., and Min, W*. (2013) AIP1 suppresses atherosclerosis progression by limiting hyperlipidemia-induced inflammation and vascular endothelial dysfunction. Arterioscler Thromb Vasc Biol. 33(4):795-804.
- Qin, L., Yu, L. and Min, W.* (2013). Mouse models for graft arteriosclerosis. J Visualized Exp (JoVE). 75, e50290.
- Wan, T., Xu, Z., Zhou, HJ, He, Y., Zhang, H., Luo, L., Li, Y., and Min, W.* (2013). Functional analyses of TNFR2 in physiological and pathological retina angiogenesis. Invest Ophthalmol Vis Sci. 54(1):211-21.
- Pasula S, Cai X, Dong Y, Messa, M, McManus J, Chang B, Liu X, Zhu H, Mansat R, Yoon S, Hahn S, Keeling J, Saunders D, Ko G, Newton G, Luscinskas F, Sun X, Towner R, Lupu, F, Xia L, Cremona O, De Camilli P, Min W.*, Chen H.*. Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling (*Min is co-corresponding author). J. Clin Invest, 122(12):4424-4438, 2012. *Also see commentary in this issue, J. Clin Invest, 122(12):4341-4343, 2012. And highlights in Nature Reviews Cancer 13: issue of January 2013.
- Truman LA, Bentley KL, Smith EC, Massaro SA, Gonzalez DG, Haberman AM, Hill M, Jones D, Min W, Krause DS, Ruddle NH. (2012) ProxTom lymphatic vessel reporter mice reveal prox1 expression in the adrenal medullar, megakaryocytes, and platelets. Am J Pathol. 180(4):1715-25
- Ji, W., Li, Y., Wan, T., Wang, J., Zhang, H., Chen, H., and Min, W*. (2012) Both internalization and AIP1 association are required for TNFR2-mediated JNK Signaling. Arterioscler Thromb Vasc Biol. 32(9):2271-9. PMCID: PMC3421067.
- Jones, D, Li, Y, He, Y, Xu, Z, Chen, H, Min W*. (2012) Mirtron microRNA-1236 inhibits VEGFR-3 signaling during inflammatory lymphangiogenesis. Arterioscler Thromb Vasc Biol. 32(3):633-42. PMCID: PMC32288963.
- Holopainen, T., Alpuche, VL., Zheng, W., Heljasvaara, R., Jones, D., He, Y., Tvorogov, D., D’Amico, G., Wiener, Z., Andersson, LC., Pihlajaniemi, T., Min, W., and Alitalo, K. (2012) Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth. Cancer Res. 72(14):3512-3521.
- Yu, L., Qin, L., Zhang, H., He, Y., Chen, H., Pober, J.S., Tellides, G., Min, W*. (2011) AIP1 prevents arteriosclerosis by inhibiting IFN-?-dependent smooth muscle cell proliferation and intimal expansion. Cir Res. 109(4):418-27. PMCID: PMC3227522.
- Xie, D., Gore, C., Zhou, J., Pong, RC, Zhang, H., Yu, L., Vessella, RL, Min, W., and Hsieh, JT (2009). DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis. Proc. Natl. Acad. Sci. USA 106(33), 13838-43. PMCID: PMC2785260.
- Louvi, A., Chen, L., Two, A., Zhang, H., Min, W., and Gunel, M (2011). Ccm3 ablation in neurovascular unit astrocytes leads to formation of cerebral cavernous malformations. Proc. Natl. Acad. Sci. USA. 108(9):3737-42. PMCID: PMC3048113.
- Wan, T., Liu, T., Zhang, H, Tang, S, and Min, W.* (2010). AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J. Biol. Chem. 285(6):3750-7. PMCID: PMC2823516.
- Xie, D., Gore, C., Liu, J., Pong, RC, Mason, R., Hao, G., Long, M., Kabbani, W., Yu, L., Zhang, H., Chen, H., Sun, X., Boothman, Min, W.*, and Hsieh, JT* (2010). DAB2IP/AIP1 modulates epithelial-to-mesenchymal transition (EMT) and metastasis in prostate cancer Proc. Natl. Acad. Sci. USA 107 (6):2485-90. (*co-corresponding authors). PMCID: PMC2823864.
- Yu, L., Ji, W., Zhang, H., Renda, MJ, He, Y., Lin, S., Cheng, E., Chen, H., Krause, DS, and Min, W.* (2010). SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis. J. Exp Med. 207(6):1183-95. PMCID: PMC2882842.
- He, Y, Zhang, H., Yu, L., Gunel, M., Boggon, T., Chen, H. and Min, W.* (2010) Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Science Signaling. 3 (116):ra26. PMCID: PMC3052863.
- Kumar A, Hou X, Lee C, Li Y, Maminishkis A, Tang Z, Zhang F, Langer HF, Arjunan P, Dong L, Wu Z, Zhu LY, Wang L, Min W, Colosi P, Chavakis T, Li X. (2010) Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation. J Biol Chem. 14;285(20):15500-10. PMCID: PMC2865282.
- Luo, Y, Xu, Z., Wan, T, He, Y, Jones, D., Zhang, H, and Min, W*. (2010) Endothelial-specific transgenesis of TNFR2 promotes adaptive arteriogenesis and angiogenesis Arterioscler Thromb Vasc Biol. 30 (7): 1307-14. PMCID: PMC2889154
- Li X, Zhang R, Zhang H, He Y, Ji W, Min W*, Boggon TJ*. (2010) Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. J Biol Chem. 285(31):24099-107 (*co-corresponding author). PMCID: PMC2911348.
- Sison, K., Eremina, V., Baelde, H., Min, W., Hirashima, M., Fantus, IG, Quaggin, SE (2010) Glomerular structure and function require paracrine, not autocrine, VEGF-VEFR2 signaling. J Am Soc Nephrol 21(10): 1691-710. PMCID: PMC3013545.
- Jones, D, Xu, Z, Zhang, H., He, Y, Kluger, M, Chen, H., and Min, W*. (2010) Functional analyses of the non-receptor kinase Bmx in VEGF-induced lymphangiogenesis. Arterioscler Thromb Vasc Biol. 30(12):2553-61. . PMCID: PMC3106279.
- Chen, H., Ko, G., Zatti, A., di Giacomo, G., Liu, L., Raiteri, E., Perucco, E., Collesi, C., Min, W., Zeiss, C., De Camilli, P. and Cremona, O (2009). Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice. Proc. Natl. Acad. Sci. USA 106(33), 13838-43. PMCID: PMC2728981.
- Li X, Ji W, Zhang R, Folta-Stogniew E, Min W, Boggon TJ. Molecular recognition of leucine-aspartate repeat (LD) motifs by the focal adhesion targeting-homology domain of cerebral cavernous malformation 3 (CCM3). J Biol Chem. 286(29):26138-47. PMCID: PMC3138288.