Mehran M. Sadeghi

Associate Professor of Medicine
Section of Cardiovascular Medicine

Research Interests

Pathobiology of Vascular Remodeling
Cardiovascular Molecular Imaging

Despite remarkable recent progress in molecular and vascular biology research, little has been achieved in adapting traditional imaging modalities to detect molecular pathobiology in vivo. Molecular imaging provides a unique opportunity to link vascular and molecular biology and imaging, ultimately leading to the development of novel imaging approaches, both for research and clinical diagnostics.

The ultimate goal of research in my laboratory is to develop novel imaging approaches to detect the molecular pathobiology of the vessel wall in vivo. Our comprehensive approach includes several components. Through basic vascular biology research we identify relevant molecular processes and potential targets for imaging (and therapeutics). Next, we use the state of the art technology to develop novel tracers targeted at relevant molecular markers, and establish molecular vascular imaging protocols in animal models of human disease. Finally, we exploit these techniques to further advance vascular biology and clinical research.

We have made significant progress towards achieving these goals in the past few years. Specifically, we have focused on vascular remodeling, as the prototypic pathological vascular process shared by many vascular diseases, including atherosclerosis, graft arteriosclerosis, post-angioplasty restenosis, and aneurysm formation. Our federally funded studies of the pathophysiology of vascular remodeling in graft arteriosclerosis, performed under the umbrella of the Interdepartmental Program in Vascular Biology and Transplantation at Yale have led to the identification novel molecular markers, including a neuropilin-like protein, ESDN, as a potential target for diagnosis and therapy of vascular remodeling. We have demonstrated that ESDN is upregulated in vascular remodeling, and have defined its function as regulator of vascular cell proliferation in vivo. We are currently in the process of defining other aspects of ESDN function, including its role in growth factor and integrin signaling pathways, and identification of ESDN ligands.

In molecular imaging arena, we have identified and validated avß3 integrin activation as a target for imaging the proliferative process in vascular remodeling, and have demonstrated the suitability of ανß3-targeted tracers for imaging graft arteriosclerosis. Matrix metalloproteinase (MMP) activation, as a key regulator of vascular remodeling, was targeted for in vivo imaging of injury-induced vascular remodeling and aneurysm formation using high resolution microSPECT imaging in conjunction with CT angiography for anatomical localization. We are currently in the process of optimizing the technical aspects of in vivo microSPECT/CT imaging to improve visualization and quantitation of molecular targets. In parallel, we have developed a novel “tracer design” concept for in vivo applications and have been involved in the development of a novel intravascular detection system which combines scintigraphy with high resolution optical coherence tomography imaging.

Recent Publications

Bender JR, Sadeghi MM, Watson C, Pfau S and Pardi R. Heterogeneous Activation Thresholds to Cytokines in Genetically Distinct Endothelial Cells; Evidence for Diverse Transcriptional Responses Proceedings of the National Academy of Sciences, USA, 1994; 91:3994-3998

Sadeghi MM, Collinge M, Pardi R, and Bender JR. Simvastatin Modulates Cytokine-Mediated Endothelial Cell Adhesion Molecule Induction; Involvement of an Inhibitory G protein, Journal of Immunology, 2000; 165: 2712-2718

Sadeghi MM, Tiglio A, Sadigh K, O’Donnell L, Collinge M, Pardi R, and Bender JR. Inhibition of Interferon--Mediated Microvascular Endothelial Cell Major Histocompatibility Complex Class II Gene Activation by HMG-CoA Reductase Inhibitors, Transplantation, 2001; 71(9): 1262-1268

Danesh FR, Sadeghi MM, Amro N, Philips C, Zeng L, Lin S, Sahai A, and Kanwar YS. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy Proceedings of the National Academy of Sciences, USA, 2002; 99:8301-8305

Tatum JL, Narula J, Bender JR, Heller G, Sadeghi MM, and Strauss HW. Lake Tahoe Invitational Meeting 2002, Panel 3: Vascular Imaging, Journal of Nuclear Cardiology, 2003; 10(2): 234-237

Zhu Q, Piao D, Sadeghi MM, and Sinusas AJ. Simultaneous optical coherence tomography imaging and beta particle detection, Optics Letters, 2003; 28(18):1704-1706.

Sadeghi MM, Schechner JS, Krassilnikova S, Gharaei AA, Zhang J, Kirkiles-Smith N, Sinusas AJ, Zaret BL and Bender JR. Vascular Cell Adhesion Molecule-1-Targeted Detection Endothelial Activation in Human Microvasculature Transplantation Proceedings, 2004; 36:1585-1591.

Sadeghi MM, Krassilnikova S, Zhang J, Gharaei AA, Rastegar Fassaei H, Esmailzadeh L, Kooshkabadi A, Edwards DS, Yalamanchili P, Harris TD, Sinusas AJ, Zaret BL, and Bender JR. "Detection of Injury-induced Vascular Remodeling by Targeting Activated alpha v beta 3 Integrin in vivo", Circulation, 2004; 110:84-90.

Meoli DF, Sadeghi MM, Krassilnikova S, Bourke B, Giordano FJ, Dione DP, Su H, Edwards DS, Liu S, Harris TD, Madri J, Zaret BL, and Sinusas AJ. Non-invasive Imaging of Myocardial Angiogenesis Following Experimental Myocardial Infarction, Journal of Clinical Investigation, 2004; 113 (12):1684-1691.

Zeng L, Xu H, Chew TL, Chisholm R, Sadeghi MM, Kanwar YS, and Danesh FR. Simvastatin Modulates Angiotensin II Signaling Pathways by Preventing Rac1-Mediated Upregulation of p27, Journal of the American society of Nephrology, 2004; 15:1711-1720.

Hua J, Dobrucki LW, , Sadeghi MM, Zhang, J, Bourke BN Cavaliere P, Song J, Chow C, Jahanshad N, Van Royen N, Buschmann I, Madri JA, Mendizabel M, and Sinusas AJ. Non-invasive Imaging of Angiogenesis with a 99mTc-labeled Peptide Targeted at avß3 Integrin Following Murine Hindlimb Angiogenesis. Circulation, 2005, 111:3255-3260.

Piao D, Sadeghi MM, Zhang J, Chen Y, Sinusas AJ, and Zhu Q. A hybrid positron detection and optical coherence tomography system: Design, calibration and experimental validation with rabbit atherosclerotic models. Journal of Biomedical Optics, 2005, 2005, 10(4):044010.

Zhang J, Krassilnikova S, Gharaei AA, Rastegar Fassaei H, Esmailzadeh L, Asadi A, Danesh FR, Edwards DS, Harris TD, Azure M, Rodriguez ER, Tellides G, Sinusas AJ, Zaret BL, Bender JR, and Sadeghi MM. avß3-targeted Imaging of Arteriopathy in Transplanted Human Coronary Arteries FASEB Journal, 2005, 19(13):1857-9.

Zeng L, Xu H, Eng E, Chew T, Sadeghi MM, Adler S, Kanwar YS, and Danesh FR. VEGF-Induced Endothelial Cell Hyperpermeability Is Mediated by Myosin Regulatory Light Chain Phosphorylation: Modulatory Effects of Statins FASEB Journal, 2005, 19(13):1845-7.

Sadeghi MM. The pathobiology of the vessel wall; implications for imaging. Journal of Nuclear Cardiology, 2006, 13(3):402-414.

Xu H, Zeng L, Peng H, Chen S, Jones J, Chew T, Sadeghi MM, Kanwar YS, and Danesh FR. HMG-CoA reductase inhibitor, simvastatin mitigates VEGF-induced inside-out signaling to extracellular matrix by preventing RhoA activation. American Journal of Physiology Renal Physiology, 2006, 291(5):F995-F1004.

Sadeghi MM and Bender, JR. Activated avß3 integrin targeting in injury-induced vascular remodeling. Trends in Cardiovascular Medicine, 2007, 17(1):5-10.

Sadeghi MM, Esmailzadeh L, Zhang J, Guo X, Asadi A, Krassilnikova S, Rastegar Fassaei H, Luo G, Al-Lamki RSM, Takahashi T, Tellides G, Bender JR, Rodriguez ER. Endothelial and Smooth Muscle Cell-derived Neuropilin-Like Protein is a marker and regulator of cell proliferation in vascular remodeling. American Journal of Transplantation, in press

Education:	M.D. Necker-Enfants Malades Faculty of Medicine, Paris, France, 1991
Training:	Residency: Yale-New Haven Hospital, 1992-1995 Clinical Cardiology Fellowship Training: YYale University, 1995-1997 Vascular Biology Fellowship: Yale University, 1997-2000

Contact

Campus Address
Department of Internal Medicine
Section of Cardiovascular Medicine
Yale University
School of Medicine
Box 208017
New Haven, CT
06520-8017

E-mail
mehran.sadeghi@yale.edu

Telephone
203.785.4114