PHA/NHLBI K08/K23 Award Winner 2012

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Edda Frauke Spiekerkoetter, MDVinicio A. de Jesus Perez, MD

Division of Pulmonary and Critical Care Medicine
Department of Medicine
Stanford University Medical Center
"The role of the Wnt/planar cell polarity pathway in pulmonary angiogenesis"
NHLBI Mentored Clinical Scientist Development Award (K08)
Term: July 1, 2012 – June 30, 2017

Summary of Research Project:

The role of the Wnt/planar cell polarity pathway in pulmonary angiogenesis

In 2012, Dr. de Jesus Perez was awarded an NIH K08 award to investigate a novel mechanism relevant to the regeneration of pulmonary vessels following injury. This is relevant to idiopathic pulmonary arterial hypertension (IPAH) as progressive narrowing and loss of small distal pulmonary arteries is a key pathological finding in all patients who are afflicted with this devastating disease.

Recent studies by our group and others have shown that mutations in the bone morphogenetic protein receptor (BMPR) II could contribute to vessel loss by reducing pulmonary artery endothelial cell (PAEC) survival and proliferation in response to injury but the mechanisms by which BMPRII can regulate these angiogenic responses have not been well characterized. In addition to PAECs, pericyte recruitment is critical for stabilization of newly formed vessels but their contribution to the pathogenesis of IPAH has not been well established. We have recently shown that BMP signaling promotes pulmonary angiogenesis by recruitment of two Wnt signaling pathways in PAECs: the “canonical” Wnt/β-catenin (βC) and the “non-canonical” Wnt/planar cell polarity (PCP) pathways.

Based on our preliminary studies and our review of the literature, we propose that activation of the Wnt/PCP pathway is required for pulmonary angiogenesis by 1) inducing PAEC to organize into properly aligned vascular tubes and 2) by promoting pericyte recruitment to vascular tubes to form functional blood vessels. In a series of experiments using PAECs and pericytes obtained from the lungs of healthy donors and IPAH patients, we will demonstrate that Wnt/PCP signaling is required to direct PAEC (Aim 1) and pericyte (Aim 2) behavior during angiogenesis and that loss of activity correlates with reduced pulmonary angiogenesis. Furthermore, we will complement these cell studies with work on two animal models of dysfunctional Wnt/PCP signaling that will help provide insight into the biological relevance of this pathway to compensatory angiogenesis following pneumonectomy (Aim 3).

Future studies will center on how mutations that reduce Wnt/PCP signaling can genetically interact with BMPRII mutations to promote development of IPAH and how therapeutic interventions aimed at normalizing Wnt/PCP pathway activity in PAEC and pericytes could help prevent progression and improve survival in IPAH patients by restoring their ability to regenerate lost vessels.

CURRICULUM VITAE

Name: Vinicio A. de Jesus Perez, MD

Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Department of Medicine
Stanford University School of Medicine
300 Pasteur Drive, Grant S140B
Stanford, CA 94305
Email: vdejesus@stanford.edu

Education/Training:

1992-1996   

University of Puerto Rico, Rio Piedras Campus, Summa cum laude
BS in Biology

1996-2000  

University of Puerto Rico Medical School, Summa cum Laude
Doctorate in Medicine

2000-2001

 

Medical Internship, Internal Medicine, Massachusetts General Hospital, Boston, MA

2001-2003  

Medical Residency, Internal Medicine, Massachusetts General Hospital, Boston, MA

2003-2004  

Fellowship, Pulmonary/Critical Care, University of Colorado Health Sciences Center, Denver, CO

2004-2006  

Fellowship, Pulmonary/Critical Care, Stanford University, Stanford, CA

2006-2007  

Fellowship, Pulmonary Vascular Medicine, Stanford University, Stanford, CA

2006-2011  

Instructor in Pulmonary/Critical Care, Stanford University, Stanford, CA

2011-  

Assistant Professor of Medicine, Stanford University, Stanford, CA

Honors

2000  Summa cum Laude, University of Puerto Rico, Rio Piedras, PR
2002  Best fellow, Denver VA Hospital, Denver, CO.
2007  Finalist, Young Investigator Award, Stanford University, Stanford, CA
2007  AHA Young Investigator Travel Award
2007  ATS Travel Award
2007  American Lung Association Career Development Award
2008  Madison's Who's Who Physician of the Year
2008  AHA Scientific Sessions Best Basic Science Abstract
2009  Finalist, Burroughs Wellcome Award.
2009  ATS Travel Award
2010  ATS Minority Travel Award
2010  NIH K12 Award in Genetics and Genomics of Lung Diseases
2011  Wall Center Genomics Award
2011  Oak Foundation Research Award
2012  Fellow, American College of Chest Physicians
2012  Member, PHA Scientific Research Committee
2012  Editor, Case Reports in Clinical Medicine
2012  Center for Biological Imaging Research Award
2012  Winner, Translation Research and Applied Medicine Award

Other Experience and Professional Memberships

2007  Member, American Heart Association (AHA)
2007  American Society for Cell Biology (ASCB)
2007  Member, American Thoracic Society (ATS)
2007  Member, American College of Chest Physicians (ACCP)
2008  Member, Latin American Pulmonary Hypertension Society.
2008  Member, North American Vascular Biology Society (NAVBO)
2008  Fellow, Pulmonary Vascular Research Institute (PVRI)
2008  Member, Pulmonary Hypertension Association (PHA)
2010  Member-at-Large, AHA 3C council
2010  Scholar, Robert Wood Johnson Foundation
2011  Member-at-Large, ATS Pulmonary Circulation Assembly
2011  Member-at-Large, ATS Lung Genomics Assembly
2012  Member, Scientific Research Committee, PHA
2012  Member, Education Committee, PHA
2012  Member, BIO-X
2012  Pulmonary Hypertension Breakthrough Initiative
2012  Member, National Scleroderma Foundation

Selected Peer Reviewed Publications

G. Hansmann, R.A. Wagner, S. Schellong, V. de Jesus Perez, T. Urashima, L. Wang, A.Y. Sheikh, R.S. Suen, D.J. Stewart, and M. Rabinovitch. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator activated receptor- activation. Circulation 2007 Mar 13; 115(10): 1275-84 (PMID: 17339547).

V. de Jesus Perez, J. Swigris and S. Ruoss. Coexistence of primary adenocarcinoma of the lung and Tsukamurella infection. Journal of Medical Case Reports 2008; 207:2 (PMID: 18554413).

V. de Jesus Perez, T.P. Alastalo, J. Wu, J. Axelrod, J. Cooke, M. Amieva and M. Rabinovitch Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta catenin and Wnt-RhoA-Rac1 pathways. Journal of Cell Biology 2009; 184:1:83-99 (PMID: 19139264).

V. de Jesus Perez, F. Haddad, R. Vagelos, W. Fearon, J. Feinstein and R.T. Zamanian. Angina Associated with left main coronary artery compression in pulmonary hypertension. Journal of Heart and Lung Transplantation, 2009; May 8(5): 527-530 (PMID: 19416787).

E. Spiekerkoetter, C. Guignabert, V. de Jesus Perez, T.P. Alastalo, J. Bekker, L. Wang, A. Lawrie, A. Schmidt, M. Berryman, R. Ashley and M. Rabinovitch. S100A4 and BMP-2 co-dependently induce smooth muscle cell migration via pERK and Chloride intracellular Channel 4.Circulation Research 2009, Sep 25; 105(7):639-47 (PMID: 19713532).

J. Wu, A. Chruscinski, V. de Jesus Perez, H. Singh, M. Pitsiouni, M. Rabinovitch, P. Utz and J. Cooke. The Cholinergic modulation of angiogenesis: role of the 7 nicotinic Acetylcholine receptor. J Cell Biochem. 2009 Oct 1; 108(2): 433-46 (PMID: 19623583).

K. T. Kudelko, K. Nadeau, A. Leung, J. Liu, F. Haddad, R.T. Zamanian and V. de Jesus Perez. Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay. J. Heart Lung Transplant 2010 29 (9): 1071-5 (PMID: 20627625).

V. de Jesus Perez, Z. Ali, T.P. Alastalo, F. Ikeno,Y. Lai, T. Kleisli, E. Spiekerkoetter, X. Qu, L.H. Rubinos, E. Ashley, M. Amieva, S. Dedhar and M. Rabinovitch. BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways. J. Cell Biol. 2011; 192 (1): 171-88 (PMID: 21220513).

V. de Jesus Perez, K.T. Kudelko, S. Snook and R.T. Zamanian. Drugs and toxins associated pulmonary arterial hypertension: lessons learned and challenges ahead. Int J Clin Pract 2011; (169): 8-10 (PMID: 21176010).

S.M. Chandra, H. Razavi, J. Kim, R. Agrawal, R. Kundu, V. de Jesus Perez, R.T. Zamanian, T. Quertermous and H. J. Chun. Arterioscler Thromb Vasc Biol 2011 Jan 13 (PMID: 21233449).

T.P. Alastalo, M. Li, V. de Jesus Perez, D. Pham, H. Sawada, J.K. Wang, M. Koskenvuo, L. Wang, B. Freeman, H. Chang and M. Rabinovitch. Disruption of PPAR?/?-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. JCI 2011, Aug 8 (PMID 21821917).

F. Haddad, E. Fuh, T. Peterson, M. Skhiri, K. Kudelko, V. de Jesus Perez, W. Wilkenmayer, R. Doyle and R.T. Zamanian. Incidence, Correlates, and Consequences of Acute Kidney Injury in Patients With Pulmonary Arterial Hypertension Hospitalized With Acute Right-Side Heart Failure. Journal of Cardiac Failure 2011 Vol 17 (7): 533-539 (PMID 21703524)

V. de Jesus Perez and R.T Zamanian. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2011 Apr 28;364(17):1677 (PMID: 21524224).

V. de Jesus Perez. Making sense of the estrogen paradox in pulmonary hypertension. AJRCCM 2011 Vol 184 (6): 629-630 (PMID: 21920924).

F. Haddad, T. Peterson, E, Fuh, K Kudelko, V. de Jesus Perez, M Skhiri, R. Vagelos , I. Schnittger, AY Denault, DN Rosenthal, R Doyle and RT Zamanian. Characteristics and outcome after hospitalization for acute right heart failure in patients with pulmonary arterial hypertension. Circ Heart Fail. 2011; 4 (6): 692-9 (PMID 21908596).

F. Haddad, K. Kudelko, O. Mercier, B. Vrtovec, RT Zamanian and V. de Jesus Perez. Pulmonary hypertension associated with left heart disease: characteristics, emerging concepts, and treatment strategies. Prog Cardiovasc Dis. 2011 Sep-Oct; 54 (2): 154-67 (PMID: 21875514).

E. Ayala, K. Kudelko, F. Haddad, R.T. Zamanian and V. de Jesus Perez. The intersection of genes and environment: development of pulmonary arterial hypertension in a patient with hereditary hemorrhagic telangiectasia and stimulant exposure. Chest. 2012; 141 (6): 1598-600 (PubMedID: 22670022).

V. de Jesus Perez, F. Haddad and R.T. Zamanian. Diagnosis and Management of pulmonary hypertension associated with left ventricular diastolic dysfunction. Pulmonary Circulation. 2012; 2 (2): 163

V. de Jesus Perez, K. Yuan, M.E. Orcholski, H. Sawada, M. Zhao, C.G. Li, N.F. Tojais, N.P. Nickel, V. Rajagopalan, E. Spiekerkoetter, L. Wang, R. Dutta, D. Bernstein and M. Rabinovitch. Loss of Adenomatous Poliposis Coli-α3 Integrin Interaction Promotes Endothelial Apoptosis in Mice and Humans. Circulation Research. 2012 Sep 25. [Epub ahead of print]

V. de Jesus Perez, E. Rosenzweig, L.J. Rubin, D. Poch, A. Bajwa, M. Park, M. Jain, R.C. Bourge, K. Kudelko, E. Spiekerkoetter, J. Liu, A. His and R.T. Zamanian. Safety and Efficacy of Transition from Systemic Prostanoids to Inhaled Treprostinil in Pulmonary Arterial Hypertension. Am J Cardiol. 2012 Jul 30. [Epub ahead of print]

 

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Last reviewed: October 2012

 

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