Vascular BiologyLaboratory

Key Research Areas

• Atherosclerosis
• Fibromuscular dysplasia
• Vascular disease, heart attack and stroke
• Spontaneous coronary artery dissection (SCAD)

Research Overview

With a research effort that spans across the Victor Chang Cardiac Research Institute and the Icahn School of Medicine at Mount Sinai in New York, our team focuses on different diseases that affect the arteries of the body. Blockages and other processes that affect the arteries cause a huge amount of disease and suffering globally – including heart attack, stroke, blockages of the leg arteries that can cause leg pain with walking, and some forms of high blood pressure and kidney failure. Our long-term goal is to make meaningful inroads into the understanding, diagnosis, treatment and prevention of vascular and cardiac disease.

There are 3 key projects underway in theVascular BiologyLaboratory, led by Professor Jason Kovacic

1. Understanding PHACTR1 - Likely the most important Gene across all Vascular Disease

The PHACTR1 (Phosphatase And Actin Regulator 1) gene is associated with fibromuscular dysplasia (FMD), SCAD, coronary artery disease, arterial dissection, hypertension, migraine headaches and more. In particular, a single nucleotide polymorphism (SNP), rs9349379, which resides in the gene encoding PHACTR1, is of particular importance to vascular disease. At this SNP, as an unusual but critical feature, regardless of which purines are present (AA, AG, or GG), a vascular disease association exists. Thus, our studies have shown at “A” at rs9349379 is associated with FMD and SCAD, while in other studies we have shown that “G” at the same SNP is associated with atherosclerotic coronary artery disease. Furthermore, there are at least 3 transcription start sites in the PHACTR1 gene and multiple isoforms are known to exist. As a result and due to this profound complexity, prior research efforts have struggled to understand this gene. Now at the VCCRI in this research effort we are bringing unique resources and knowledge to address this problem, and are working to systematically understand PHACTR1 and its causative mechanisms.

2. Investigating the Link Between FMD and SCAD

SCAD and FMD are very closely related and our team at Mount Sinai has played a key role in unravelling the causes of these diseases. Partly in collaboration with Professor Bob Graham and his team, this work is being continued in a major international effort.

3. Understanding Vascular Disease through Systems Biology

In a collaborative effort spanning Australia, Europe and the USA, we are key partners in a multi-national team that has spearheaded efforts to understand vascular diseases using powerful and “systems biology” techniques.

*As separate projects, Prof Kovacic’s team at the Icahn School of Medicine at Mount Sinai are also engaged in additional research efforts in the area of vascular disease.

Internal

Molecular Cardiology Laboratory
Prof Bob Graham, Lab Head
Dr Siiri Iismaa, Senior Scientist

Computational Genomics Laboratory
A/Prof Eleni Giannoulatou, Lab Head

Vascular Epigenetics Laboratory
Dr Renjing Liu, Lab Head

National Collaborators

Alex Brown, South Australian Health and Medical Research Institute (SAHMRI), Australia

Gemma Figtree, University of Sydney and The Kolling Institute of Medical Research, Australia

Steve Nicholls, Monash University and Victorian Heart Hospital, Australia

International Collaborators

Jeffrey Olin, Icahn School of Medicine at Mount Sinai, USA

Daniela Kadian-Dodov, Icahn School of Medicine at Mount Sinai, USA

Maria-Paola Santini, Icahn School of Medicine at Mount Sinai, USA

Manuel Mayr, Icahn School of Medicine at Mount Sinai, USA

Ke Hao, Icahn School of Medicine at Mount Sinai, USA

Valentin Fuster, Icahn School of Medicine at Mount Sinai, USA

Kevin Costa, Icahn School of Medicine at Mount Sinai, USA

Johan L.M. Björkegren, Icahn School of Medicine at Mount Sinai, USA

Mary Weiser-Evans, University of Colorado Anschutz Medical Campus, USA

Manfred Boehm, National Institutes of Health, USA

Santhi Ganesh, University of Michigan Medical School, USA

Clint Miller, University of Virginia School of Medicine, USA

David Adlam, Glenfield Hospital, UK

Nabila Bouatia-Naji, Universite de Paris, France

Andrew Baker, University of Edinburgh, Scotland

1. Kovacic JC, Macdonald P, Feneley MP, Muller DWM, Freund J, Dodds A, Milliken S, Tao H, Itescu S, Moore J, Ma D, Graham RM. Safety and efficacy of consecutive cycles of granulocyte-colony stimulating factor, and an intracoronary CD133+ cell infusion in patients with chronic refractory ischemic heart disease: the GAIN I trial. Am Heart J. 2008; 156: 954-63.
2. Kovacic JC, Gupta R, Lee AC, Ma M, Fang F, Tolbert CN, Walts AD, Beltran LE, San H, Chen G, St. Hilaire C, Boehm M. STAT3-dependent acute RANTES production in vascular smooth muscle cells modulates inflammation following arterial injury. J Clin Invest. 2010; 120: 303-14.
3. Kovacic JC, Lee P, Baber U, Karajgikar R, Evrard SM, Moreno P, Mehran R, Fuster V, Dangas G, Sharma S, Kini A. Inverse relationship between body mass index and coronary artery calcification in patients with clinically significant coronary lesions. Atherosclerosis 2012; 211: 176-82.
4. Dangas GD, Maehara A, Evrard SM, Sartori S, Li JR, Chirumamilla AP, Kitabaysahi A, Gukathasan N, Hassanin A, Baber U, Fahy M, Fuster V, Mintz GS, Kovacic JC. Coronary artery calcification is inversely related to body morphology in patients with significant coronary artery disease: a 3-dimensional intravascular ultrasound study. Eur Heart J Cardiovasc Imaging. 2014; 15(2): 201-9.
5. Cooley C, Nevado J, Mellad J, Yang D, St. Hilaire C, Negro A, Fang F, Chen G, San H, Walts AD, Schwartzbeck RL, Taylor B, Lanzer JD, Wragg A, Elagha A, Beltran LE, Berry C, Feil R, Virmani R, Ladich E, Kovacic JC, Boehm M. TGF-β signaling mediates endothelial to mesenchymal transition (EndMT) during vein graft remodeling. Sci Transl Med. 2014; 6(227): 227ra34.
6. Michelis KC, Olin JW, Kadian-Dodov D, d’Escamard V, Kovacic JC. Coronary Artery Manifestations of Fibromuscular Dysplasia. J Am Coll Cardiol. 2014; 64(10): 1033-1046.
7. Evrard SM*, Lecce L*, Michelis KC, Nomura-Kitabayashi A, Pandey G, Purushothaman KR, d’Escamard V, Li JR, Hadri L, Fujitani K, Moreno PR, Benard L, Rimmele P, Cohain A, Mecham B, Randolph GJ, Nabel EG, Hajjar R, Fuster V, Kovacic JC. Endothelial-To-Mesenchymal Transition Is Common In Advanced Atherosclerotic Lesions And Is Associated With Plaque Instability. Nat Commun. 2016 Jun 24;7:11853. doi: 10.1038/ncomms11853. *Equal contribution.
8. Kiando SR, Tucker NR, Castro-Vega LJ, Katz A, D’Escamard V, Tréard C, Fraher D, Albuisson J, Kadian-Dodov D, Ye Z, Austin E, Yang ML, Hunker K, Barlassina C, Cusi D, Galan P, Empana JP, Jouven X, Gimenez-Roqueplo AP, Bruneval P, Kim ESH, Olin JW, Gornik HL, Azizi M, Plouin PF, Ellinor PT, Kullo IJ, Milan DJ, Ganesh SK, Boutouyrie P, Kovacic JC, Jeunemaitre X, Bouatia-Naji N. PHACTR1 Is A Genetic Susceptibility Locus For Fibromuscular Dysplasia; Supporting Its Complex Genetic Pattern of Inheritance. PLoS Genet. 2016; 12(10): e1006367.
9. Dweck MR, Abgral R, Trivieri MG, Robson PM, Karakatsanis N, Mani V, Palmisano A, Miller M, Lala A, Chang HL, Sanz J, Contreras J, Narula J, Fuster V, Padilla M, Fayad ZA, Kovacic JC. Hybrid MR/PET Imaging with FDG to Diagnose Active Cardiac Sarcoidosis. JACC Cardiovasc Imaging. 2018; 11: 94–107.
10. Michelis KC, Nomura-Kitabayashi A, Lecce L, Franzén O, Koplev S, Xu Y, Santini MP, D’Escamard V, Lee JTL, Fuster V, Hajjar R, Reddy R, Chikwe J, Stelzer P, Filsoufi F, Stewart A, Anyanwu A, Björkegren JLM, Kovacic JC. CD90 Identifies adventitial mesenchymal progenitor cells in adult human medium- and large-sized arteries. Stem Cell Reports. 2018; 11: 242-57.
11. Kovacic JC, Dimmeler S, Harvey RP, Finkel T, Aikawa E, Krenning G, Baker A. Endothelial to Mesenchymal Transition in Cardiovascular Disease. J Am Coll Cardiol. 2019; 73(2): 190-209.
12. Santini MP, Malide D, Hoffman G, Pandey G, D’Escamard V, Nomura-Kitabayashi A, Rovira I, Kataoka H, Ochando J, Harvey RP, Finkel T, Kovacic JC. Tissue-resident PDGFRα⁺ progenitor cells contribute to fibrosis versus healing in a context- and spatiotemporally-dependent manner. Cell Rep. 2020; 30(2): 555-570.e7.
13. Olin JW,* Di Narzo AF,* d’Escamard V,* Kadian-Dodov D,* Cheng H, Georges A, King A, Thomas A, Barwari T, Michelis KC, Bouchareb R, Bander E, Anyanwu A, Stelzer P, Filsoufi F, Florman S, Civelek M, Debette S, Jeunemaitre X, Björkegren JLM, Mayr M, Bouatia-Naji N, Hao K, Kovacic JC. A Plasma Proteogenomic Signature for Fibromuscular Dysplasia. Cardiovasc Res. 2020; 116(1): 63-77. *Equal contribution.
14. Ma L, Chandel N, Ermel R, Sukhavasi K, Hao K, Ruusalepp A, Björkegren JLM, Kovacic JC. Multiple independent mechanisms link gene polymorphisms in the region of ZEB2 with risk of coronary artery disease. Atherosclerosis. 2020; 311: 20-29.
15. Georges A, Yang ML, Berrandou TE, Bakker MK, Dikilitas O, Kiando SR, Ma L, Satterfield BA, Sengupta S, Yu M, Deleuze JF, Dupré D, Hunker KL, Kyryachenko S, Liu L, Sayoud-Sadeg I, Amar L, Brummett CM, Coleman DM, d'Escamard V, de Leeuw P, Fendrikova-Mahlay N, Kadian-Dodov D, Li JZ, Lorthioir A, Pappaccogli M, Prejbisz A, Smigielski W, Stanley JC, Zawistowski M, Zhou X, Zöllner S; FEIRI investigators; International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group; MEGASTROKE, Amouyel P, De Buyzere ML, Debette S, Dobrowolski P, Drygas W, Gornik HL, Olin JW, Piwonski J, Rietzschel ER, Ruigrok YM, Vikkula M, Warchol Celinska E, Januszewicz A, Kullo IJ, Azizi M, Jeunemaitre X, Persu A, Kovacic JC, Ganesh SK, Bouatia-Naji N. Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases. Nat Commun. 2021 Oct 15;12(1):6031. doi: 10.1038/s41467-021-26174-2.
16. Lecce L,* Xu Y,* V’Gangula B, Chandel N, Pothula V, Caudrillier A, Santini MP, d’Escamard V, Ceholski DK, Gorski PA, Ma L, Koplev S, Bjørklund MM, Björkegren JLM, Boehm M, Bentzon JF, Fuster V, Kim HW, Weintraub NL, Baker AH, Bernstein E, Kovacic JC. Histone deacetylase 9 promotes endothelial to mesenchymal transition and an unfavorable atherosclerotic plaque phenotype. J Clin Invest. 2021; 131(15): e131178. *Equal contribution.