Vascular Epigenetics Laboratory

Key Research Areas

• Vascular smooth muscle
  
• Epigenetics
• Cellular plasticity

Research Overview

Vascular smooth muscle cells are the main cell type found in blood vessel walls responsible for blood vessel wall contraction. They are also remarkably plastic, and can “switch” between phenotypes for vascular repair or contribute to cardiovascular pathologies including intimal hyperplasia (precursor to atherosclerosis and stroke), aortic aneurysms, vascular calcification.

The main focus of the Vascular Epigenetics Laboratory is to develop ways to effectively reprogram the disease-causing vascular smooth muscle cells back to their physiological state. This research will have immense implications for reducing cardiovascular morbidity and mortality. Our research combines advances in cellular and molecular techniques with cutting-edge sequencing technology, and the generation of sophisticated genetic mouse models mimicking human diseases.

There are 3 key projects underway in the Vascular Epigenetics Laboratory, led by Dr Renjing Liu;

1. Basic mechanisms regulating vascular smooth muscle cell plasticity
2. Epigenetic reprogramming of calcified vascular smooth muscle cells
3. Genetic and epigenetic basis of aortic aneurysms

1. Basic mechanisms regulating vascular smooth muscle cell plasticity

Inappropriate dedifferentiation and proliferation of vascular smooth muscle cells, a phenomenon known as “phenotypic plasticity”, is the key underlying cause of many cardiovascular diseases including atherosclerosis, hypertension and aortic aneurysms. The Liu Lab has now uncovered a novel stemness gene network that may in part be responsible for the plasticity of smooth muscle cells. Ongoing studies are aimed at understanding how this stemness pathway is regulated and can be manipulated for therapeutic purposes.

2. Epigenetic reprogramming of calcified vascular smooth muscle cells

Vascular calcification, or the deposition of bone-like minerals in the arterial wall, is associated with increased risks of developing heart disease, atherosclerosis and stroke. Calcification of blood vessels is driven in part by the irreversible transdifferentiation of contractile vascular smooth muscle cells to an osteo/chondrogenic phenotype. We have previously identified a novel epigenetic “switch” that can turn vascular smooth muscle cells from the highly proliferative disease-causing cell fate to the physiological contractile phenotype. This Project will expand upon these initial findings, and determine whether this epigenetic switch can revert the bone-forming cell type back to a contractile cell fate.

3. Genetic and epigenetic basis of aortic aneurysms

Aortic aneurysm is a pathological condition characterised by weakening of the vessel wall that eventually leads to rupture and premature death. Treatments for this disease are currently limited to surgical interventions that are associated with high morbidity and mortality. We have recently identified a novel DNA demethylase that is protective against the initiation and development of aortic dissections and aneurysms. Excitedly, we have now identified novel genetic variants of this gene that may predispose individuals to aortic aneurysms. Current studies are using gene therapy or repurposed and/or newly identified drugs to reduce aortic aneurysm development and progression in animal models, as well as deciphering the significance of genetic variants to aortic aneurysm formation and development.

1. Wang R, Wu ST, Yang X, Qian Y, Choi JP, Gao R, Song S, Wang Y, Zhuang T, Wong JJL, Zhang Y, Han Z, Lu HA, Alexander SI, Liu R, Xia Y, Zheng X. Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting. JCI Insight, 6(12):e142838, 2021.
2. Zeng Z, Xia L, Fan S, Zheng J, Qin J, Fan X, Liu Y, Tao J, Liu Y, Li K, Ling Z, Bu Y, Martin KA, Hwa J, Liu R, Tang WH. Circular RNA CircMAP3K5 Acts as a MicroRNA22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation. Circulation, 143(4):354-371, 2020.
3. Zeng Z, Xia L, Fan X, Ostriker AC, Yarovinsky T, Su M, Zhang Y, Peng X, Xie Y, Pi L, Gu X, Chung SK, Martin KA, Liu R, Hwa J, Tang WH. Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair. Journal of Clinical Investigations, 129:1372-1386, 2019.
4. Cakouros D, Hemming S, Gronthos K, Liu R, Zannettino A, Shi S, Gronthos S. Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination. Epigenetic & Chromatin, 12:3, 2019.
5. Choi JP, Wang R, Yang X, Wang X, Wang L, Ting KK, Foley M, Cogger V, Yang Z, Liu F, Han Z, Liu R, Baell J, Zheng X. Ponatinib (AP24534) inhibits MEKK3-KLF signalling and prevents formation and progression of cerebral cavernous malformations. Science Advances, 4:eaau0731, 2018.
6. Liu R*, Lo L, Lay AJ, Robertson EN, Sherrah AG, Zhou Z, Li H, Richmond DR, Hambly BD, Jeremy RW, Bannon PG, Vadas V, Gamble JR*. ARHGAP18 protects against thoracic aortic aneurysm formation by mitigating the synthetic and pro-inflammatory smooth muscle cell phenotype. Circulation Research, 121:512-524, 2017.
7. Jin Y, Xie Y, Ostriker AC, Zhang X, Liu R, Lee M, Leslie KL, Tang W, Du J, Lee SH, Wang Y, Sessa WC, Hwa J, Yu JMartin KA. Opposing actions of AKT isoforms in vascular smooth muscle injury response and therapeutic mTORC1 inhibition. Arterioscler Thromb Vasc Biol 37:2311-2321, 2017.
8. Liu R, Leslie KL, Martin KA. Epigenetic Regulation of Smooth Muscle Cell Plasticity. BBA – Gene Regulatory Mechanisms. 1849:448-453, 2015.
9. Tang W, Stitham J, Jin Y, Liu R, Lee SH, Du J, Atteya G, Gleim S, Spollett G, Martin KA, Hwa J. Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. Circulation. 129:1598-609, 2014.
10. Zhou HJ, Chen X, Huang Q, Liu R, Zhang H, Wang Y, Jin Y, Liang X, Lu L, Xu Z, Min W. AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses. Arterioscler Thromb Vasc Biol. 34:603-15, 2014.
11. Liu R, Jin Y, Tang W, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA. TET2 is an mTORC1-dependent master regulator of vascular smooth muscle plasticity. Circulation, 128:2047-57, 2013.
12. Qin L, Zhang H, Liu R, Tellides G, Min W, Yu L. SOSC1 prevents graft arteriosclerosis by preserving endothelial cell function. J Am Coll Cardiol, 63:21-9, 2013.