Rong Wang, PhD
Molecular Regulation of Arterial-Venous Programming in Development and Disease
Research in my lab is focused on angiogenesis, or new blood vessel formation, which is a critical process in development and disease. My lab aims to advance the fundamental understanding of the cellular, molecular, and hemodynamic mechanisms underlying arterial-venous programming in normal and pathological angiogenesis. We use cutting-edge mouse genetics to delete or express genes in a cell lineage-specific and temporally controllable fashion in endothelial cells. This advance is crucial for the study of candidate genes in vascular function, especially when combined with sophisticated 5D two-photon imaging (3D + blood flow over time). These innovative approaches provide us with exceptional access to gene function in both healthy and pathological conditions in living animals. This basic approach is complemented by preclinical studies with patient samples in addition to our mouse models of disease. In particular, we investigate the molecular regulators governing arterial-venous programming – particularly the Notch, ephrin-B2, and TGF-beta signaling pathways – in both normal and pathological conditions.
Vascular Development. Our lab aims to identify molecular regulators of arterial and venous cell fate determination and morphogenesis in embryonic development. We primarily focus on the origin and morphogenesis of the dorsal aorta and cardinal vein, the first major artery-vein pair to form in the body.
Arteriovenous Malformation (AVM). AVMs are severe vascular anomalies that shunt blood directly from arteries to veins, displace intervening capillaries, and bypass tissues. My lab studies the pathogenesis and regression of AVMs. We have a long history of investigation using animal models into Notch-mediated AVM pathogenesis as well as into potential treatments for the disease.
Arterial occlusive diseases and arteriogenesis. The body responds to arterial occlusions by inducing arteriogenesis, or radial enlargement of arteries, to restore circulation to blood-deprived tissue. We are investigating pro-arteriogenic molecular regulators to uncover potential therapeutic targets, which may be used to enhance the body’s natural defense against arterial occlusive disease.
Cancer. Solid tumors induce arteriogenesis to support their growth. We investigate the molecular stimulators of arteriogenesis in tumor progression and regression, particularly in hepatocellular carcinoma (HCC), which is characterized by large and highly arterialized tumor masses in the liver. We study genes regulating tumor arterial growth and modify these genes to target tumor arterial supply and to inhibit HCC growth.
Ultimately, through these distinct but interconnected fields of study, we hope to identify novel drug targets and inform rational design of new therapeutics to treat human disease.
- Cuervo H, Nielsen CM, Simonetto DA, Ferrell L, Shah VH, Wang RA. Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice. Hepatology. 2016 Oct; 64(4):1302-16.
- Nielsen CM, Huang L, Murphy PA, Lawton MT, Wang RA. Mouse Models of Cerebral Arteriovenous Malformation. Stroke. 2016 Jan; 47(1):293-300.
- Murphy PA, Kim TN, Huang L, Nielsen CM, Lawton MT, Adams RH, Schaffer CB, Wang RA. Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proc Natl Acad Sci U S A. 2014 Dec 16; 111(50):18007-12.
- Lin Y, Jiang W, Ng J, Jina A, Wang RA. Endothelial ephrin-B2 is essential for arterial vasodilation in mice. Microcirculation. 2014 Oct; 21(7):578-86.
- Nielsen CM, Cuervo H, Ding VW, Kong Y, Huang EJ, Wang RA. Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice. Development. 2014 Oct; 141(19):3782-92.
- Lindskog H, Kim YH, Jelin EB, Kong Y, Guevara-Gallardo S, Kim TN, Wang RA. Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals. Development. 2014 Mar; 141(5):1120-8.
- Costa MJ, Wu X, Cuervo H, Srinivasan R, Bechis SK, Cheang E, Marjanovic O, Gridley T, Cvetic CA, Wang RA. Notch4 is required for tumor onset and perfusion. Vasc Cell. 2013; 5(1):7.
- Kim TN, Goodwill PW, Chen Y, Conolly SM, Schaffer CB, Liepmann D, Wang RA. Line-scanning particle image velocimetry: an optical approach for quantifying a wide range of blood flow speeds in live animals. PLoS One. 2012; 7(6):e38590.
- Murphy PA, Kim TN, Lu G, Bollen AW, Schaffer CB, Wang RA. Notch4 normalization reduces blood vessel size in arteriovenous malformations. Sci Transl Med. 2012 Jan 18; 4(117):117ra8.
- Miniati D, Jelin EB, Ng J, Wu J, Carlson TR, Wu X, Looney MR, Wang RA. Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice. Am J Physiol Lung Cell Mol Physiol. 2010 Feb; 298(2):L169-77.
- Herbert SP, Huisken J, Kim TN, Feldman ME, Houseman BT, Wang RA, Shokat KM, Stainier DY. Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science. 2009 Oct 9; 326(5950):294-8.
- Murphy PA, Lu G, Shiah S, Bollen AW, Wang RA. Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease. Lab Invest. 2009 Sep; 89(9):971-82.
- Yang Y, Tang G, Yan J, Park B, Hoffman A, Tie G, Wang R, Messina LM. Cellular and molecular mechanism regulating blood flow recovery in acute versus gradual femoral artery occlusion are distinct in the mouse. J Vasc Surg. 2008 Dec; 48(6):1546-58.
- Kim YH, Hu H, Guevara-Gallardo S, Lam MT, Fong SY, Wang RA. Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis. Development. 2008 Nov; 135(22):3755-64.
- Murphy PA, Lam MT, Wu X, Kim TN, Vartanian SM, Bollen AW, Carlson TR, Wang RA. Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice. Proc Natl Acad Sci U S A. 2008 Aug 5; 105(31):10901-6.
- Dubois NC, Adolphe C, Ehninger A, Wang RA, Robertson EJ, Trumpp A. Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function. Development. 2008 Aug; 135(14):2455-65.
- He C, Hu H, Braren R, Fong SY, Trumpp A, Carlson TR, Wang RA. c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo. Development. 2008 Aug; 135(14):2467-77.
- Carlson TR, Hu H, Braren R, Kim YH, Wang RA. Cell-autonomous requirement for beta1 integrin in endothelial cell adhesion, migration and survival during angiogenesis in mice. Development. 2008 Jun; 135(12):2193-202.
- Tward AD, Jones KD, Yant S, Cheung ST, Fan ST, Chen X, Kay MA, Wang R, Bishop JM. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci U S A. 2007 Sep 11; 104(37):14771-6.
- Braren R, Hu H, Kim YH, Beggs HE, Reichardt LF, Wang R. Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation. J Cell Biol. 2006 Jan 2; 172(1):151-62.
- Yan J, Tang GL, Wang R, Messina LM. Optimization of adenovirus-mediated endothelial nitric oxide synthase delivery in rat hindlimb ischemia. Gene Ther. 2005 Nov; 12(22):1640-50.
- Proctor JM, Zang K, Wang D, Wang R, Reichardt LF. Vascular development of the brain requires beta8 integrin expression in the neuroepithelium. J Neurosci. 2005 Oct 26; 25(43):9940-8.
- Carlson TR, Yan Y, Wu X, Lam MT, Tang GL, Beverly LJ, Messina LM, Capobianco AJ, Werb Z, Wang R. Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci U S A. 2005 Jul 12; 102(28):9884-9.
- Carpenter B, Lin Y, Stoll S, Raffai RL, McCuskey R, Wang R. VEGF is crucial for the hepatic vascular development required for lipoprotein uptake. Development. 2005 Jul; 132(14):3293-303.
- Tang GL, Chang DS, Sarkar R, Wang R, Messina LM. The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia. J Vasc Surg. 2005 Feb; 41(2):312-20.
- Tward AD, Jones KD, Yant S, Kay MA, Wang R, Bishop JM. Genomic progression in mouse models for liver tumors. Cold Spring Harb Symp Quant Biol. 2005; 70:217-24.
- Tang G, Charo DN, Wang R, Charo IF, Messina L. CCR2-/- knockout mice revascularize normally in response to severe hindlimb ischemia. J Vasc Surg. 2004 Oct; 40(4):786-95.
- Chang DS, Su H, Tang GL, Brevetti LS, Sarkar R, Wang R, Kan YW, Messina LM. Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb. Mol Ther. 2003 Jan; 7(1):44-51.
- Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM. Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol. 2001 May 28; 153(5):1023-34.
- Wang R, Kobayashi R, Bishop JM. Cellular adherence elicits ligand-independent activation of the Met cell-surface receptor. Proc Natl Acad Sci U S A. 1996 Aug 6; 93(16):8425-30.
- Wang R, Siegal GP, Scott DL, Bautch VL. Developmental analysis of bone tumors in polyomavirus transgenic mice. Lab Invest. 1994 Jan; 70(1):86-94.
- Wang R, Clark R, Bautch VL. Embryonic stem cell-derived cystic embryoid bodies form vascular channels: an in vitro model of blood vessel development. Development. 1992 Feb; 114(2):303-16.
- Wang R, Bautch VL. The polyomavirus early region gene in transgenic mice causes vascular and bone tumors. J Virol. 1991 Oct; 65(10):5174-83.
- Dubois NA, Kolpack LC, Wang R, Azizkhan RG, Bautch VL. Isolation and characterization of an established endothelial cell line from transgenic mouse hemangiomas. Exp Cell Res. 1991 Oct; 196(2):302-13.