Molecular Signaling in Epigenetic and Transcriptional Regulation of Endothelial Cell Differentiation and Angiogenesis

Angiogenesis associated with endothelial cell differentiation plays a vital role in growth and development, wound healing, ischemic cardiovascular disease, cancer, and the cardiovascular complications of diabetes, while also contributing to the progression of arthritis and psoriasis. An angiogenic switch critical to angiogenesis is regulated by a dynamic balance between pro- and anti-angiogenic signaling, in which angiogenic receptors are important players. Our studies suggest that lysophosphatidic acid (LPA, a lipid signaling mediator), protein kinase D (PKD-1, also known as PKCmu), and the transcription factor FoxO1 coordinate and integrate the signaling essential for regulating endothelial cell differentiation. This turns on an angiogenic switch, thereby initiating angiogenesis and promoting vascular maturation via epigenetic and transcriptional repression of CD36 (an angiogenic regulator and fatty acid receptor). The endpoint is enhanced microvascular remodeling and functional angiogenesis. The objectives of the Ren Lab are to understand how microvascular endothelial cells differentiate into arteriolar endothelial cells via the LPA/PKD-1-FoxO1-CD36 signaling axis, and how this process of transdifferentiation is associated with functional angiogenesis and capillary arterialization under ischemic and other pathological conditions and serves as a unique vascular niche for the maintenance and self-renewal of cancer stem cells (CSCs) or tumor initiating cells (TICs).

Selected Publications

  1. Ren B, Yee KO, Lawler J, Khosravi-Far R*. Regulation of tumor angiogenesis by thrombospondin-1. Biochimca et Biophysica Acta 2006; 1765 (2): 178-188. PMID: 1640667. (Invited review).
  2. Ren B, Song K, Parangi S, Jin T, Ye M, Humphreys R, Duquette M, Benhaga N, Lawler J, Khosravi-Far R*. A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR. Cancer Research 2009; 69 (9): 3856–65. PMCID: PMC2981788. (*Corresponding author)
  3. Ren B, Hale J, Srikanthan S, Silverstein R*. Lysophosphatidic acid suppresses endothelial cell CD36 expression and promotes angiogenesis via a PKD-1 dependent signaling pathway. Blood, 2011; 117:6036-6045. PMCID: PMC3112047. (*Corresponding author)
  4. Dong L, Yuan Y, Opansky C, Chen Y, Aguilera-Barrantes I, Wu S, Yuan R, Cao Q, Cheng YC, Sahoo D, Silverstein RL, Ren B*. Diet-induced obesity links to ER positive breast cancer progression via LPA/PKD-1-CD36 signaling-mediated microvascular remodeling. Oncotarget, 2017; 8(14): 22550–22562. PMCID: PMC5410244. (*Corresponding author).
  5. Abdellah Akil, Ana K. Gutiérrez-García, Rachael Guenter, J. Bart Rose, Adam Beck, Herbert Chen, Bin Ren. Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective. Frontiers in Cell and Developmental Biology, 2021.

Arteriolar Differentiation and de novo Arteriogenesis

Tissue viability requires adequate arterial blood supply and tissue perfusion to provide sufficient oxygen and nutrients to satisfy the metabolic demands of cells under physiological and pathological conditions. Arteriogenesis, the process by which new functional arteries are formed, is the most efficient means of enhancing tissue perfusion during arterial occlusion. However, this process is dysfunctional in certain pathological conditions. There are no effective therapeutic strategies to promote normal development of functional blood vessels. When working with Drs. Michael Simons and Roy Silverstein and collaborating with Dr. Randal Peterson, Dr. Ren demonstrated that MAP kinase/ERK signaling pathway plays a pivotal role in arterial differentiation by accompanying inhibition of PI3K/AKT signaling in endothelial cells. Through continued collaboration with Drs. Silverstein and Peterson, Dr. Ren demonstrated that the LPA/PKD-1-CD36 signaling axis regulates arteriolar differentiation and functional angiogenesis, in which FoxO1 and small chemical molecules such as GS4012 and GS4898 may play critical roles. Currently the Ren Lab is actively studying mechanisms of arteriolar differentiation and capillary arterialization via an epigenetic and transcriptional signaling pathway. His work is among the first to illuminate several inadequately explored and poorly understood aspects of vascular biology and angiogenesis, including those critical to ischemic vascular disease, cerebral vascular disease, and tumor growth and metastasis. The use of cellular and molecular tools in established models of endothelial cells, stem cells and cancer stem-like cells, and integrating unique genetically engineered animal models in his Lab will facilitate the discovery of innovative pathways important in functional angiogenesis and define arteriolar angiogenesis functioning as a unique vascular niche for cancer stem cells to provide valuable insights into the development of novel effective therapeutic strategies against a variety of diseases associated with vascular pathology such as cancer, ischemic cardiovascular disease and Alzheimer’s disease.

Selected Publications

1. Ren B, Deng Y, Mukhopadhyay A, Lanahan AA, Zhuang ZW, Moodie KL, Mulligan-Kehoe MJ, Byzova TV, Peterson RT, Simons M*. Erk1/2-Akt1 cross-talk-dependent regulation of arteriogenesis. Journal of Clinical Investigation 2010; 120 (4):1217–1228. PMCID: PMC2846043 (*Corresponding author)

2. Ren B*, Best B, Ramakrishnan D, Walcott B, Storz P, Silverstein R. LPA/PKD-1-FoxO1 signaling axis mediates endothelial cell CD36 transcriptional repression, proangiogenic and proarteriogenic reprogramming. Arterioscler Thromb Vasc Biol, 2016; 36:1197-1208. PMCID: PMC 4882231. (*Corresponding author, and chosen for cover).

3. Best B, Moran P, Ren B*. VEGF/PKD-1 signaling mediates arteriogenic gene expression and angiogenic responses in reversible human microvascular endothelial cells with extended lifespan. Mol Cell Biochem. 2018 Sep;446(1-2):199-207. doi: 10.1007/s11010-018-3286-z. [Epub ahead of print] (*Corresponding author)

4. Ren B*. FoxO1 transcriptional activities in VEGF expression and beyond: a key regulator in functional angiogenesis? J Pathol. 2018; 245(3):255-257. doi: 10.1002/path.5088. (*Corresponding author)

5. Yinan Jiang, Hailey Guo, … Roy Silverstein, Bin Ren. Development of an arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic acid/protein kinase D signaling. Communications Biology (Nature), 2021.