Vascular Epigenetics Laboratory

Key Research Areas

• Vascular smooth muscle cells
• Epigenetic regulation
• Vascular diseases

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 4 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
4. Understanding a novel mechanosensing pathway in vascular cell

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.

4. Understanding a novel mechanosensing pathway in vascular cells

Many cardiovascular diseases originate from altered mechanosensing. Vascular cells, such as vascular smooth muscle cells and endothelial cells, are highly mechano-sensitive and their functions and activities are significantly influenced by mechanical signals. In collaboration with the Cox Lab at VCCRI, we are investigating the role of a novel mechanosensitive ion channel in various cardiovascular diseases, including aortic aneurysms and vascular calcification. We are deciphering a pathway to understand how signals from the cell surface are relayed to the nucleus, resulting in changes in gene expression that ultimately lead to cardiovascular conditions.

1. Wen Y, Liu Y, Li Q, Tan J, Fu X, Liang Y, Tuo Y, Liu L, Zhou X, LiuFu D, Fan X, Chen C, Chen Z, Wang Z, Fan S, Liu R, Pan L, Zhang Y and Tang WH. Spatiotemporal ATF3 Expression Determines VSMC Fate in Abdominal Aortic Aneurysm. Circ Res. 2024.
2. Yang X, Wu ST, Gao R, Wang R, Wang Y, Dong Z, Wang L, Qi C, Wang X, Schmitz ML, Liu R, Han Z, Wang L and Zheng X. Release of STK24/25 suppression on MEKK3 signaling in endothelial cells confers cerebral cavernous malformation. JCI insight. 2023;8.
3. Su M, Chen C, Li S, Li M, Zeng Z, Zhang Y, Xia L, Li X, Zheng D, Lin Q, Fan X, Wen Y, Liu Y, Chen F, Luo W, Bu Y, Qin J, Guo M, Qiu M, Sun L, Liu R, Wang P, Hwa J and Tang WH. Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis. Nat Cardiovasc Res. 2022;1:732-747.
4. Bax M, Romanov V, Junday K, Giannoulatou E, Martinac B, Kovacic JC, Liu R, Iismaa SE and Graham RM. Arterial dissections: Common features and new perspectives. Frontiers in cardiovascular medicine. 2022;9:1055862.
5. 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 and Tang WH. Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation. Circulation. 2021;143:354-371.
6. 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 and Tang WH. Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair. J Clin Invest. 2019;129:1372-1386.
7. 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 and Zheng X. Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations. Science advances. 2018;4:eaau0731.
8. Zhang C, Syed TW, Liu R and Yu J. Role of Endoplasmic Reticulum Stress, Autophagy, and Inflammation in Cardiovascular Disease. Frontiers in cardiovascular medicine. 2017;4:29.
9. Liu R, Lo L, Lay AJ, Zhao Y, Ting KK, Robertson EN, Sherrah AG, Jarrah S, Li H, Zhou Z, Hambly BD, Richmond DR, Jeremy RW, Bannon PG, Vadas MA and Gamble JR. ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype. Circ Res. 2017;121:512-524.
10. Liu R, Leslie KL and Martin KA. Epigenetic regulation of smooth muscle cell plasticity. Biochim Biophys Acta. 2015;1849:448-53.
11. Qin L, Huang Q, Zhang H, Liu R, Tellides G, Min W and Yu L. SOCS1 prevents graft arteriosclerosis by preserving endothelial cell function. J Am Coll Cardiol. 2014;63:21-9.
12. Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J and Martin KA. Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation. 2013;128:2047-2057.