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 as well as an innate immunity receptor). The endpoint is enhanced microvascular remodeling and functional angiogenesis as well as arteriolar 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, arteriolar 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.
  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. 
  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. 
  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.
  6. Adam W. Beck, Herbert Chen and Bin Ren*. Arteriolar angiogenesis: implications in anti-angiogenic immunotherapy for pancreatic cancers, Cytokine and Growth Factor Reviews, Volume 86, December 2025, Pages 96-107. doi: https://doi.org/10.1016/j.cytogfr.2025.10.002 (invited review).

Arteriolar Differentiation and Arteriolar Angiogenesis

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 Dr. Michael Simons at Dartmouth Medical School and Dr. Roy Silverstein at Cleveland Clinic and collaborating with Dr. Randal Peterson at Harvard Medical School, 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 Dr. Roy Silverstein at MCW and Dr. Randall Peterson in the College of Pharmacy, University of Utah, 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. Based upon his and other studies, he has recently proposed and developed a new concept of arteriolar angiogenesis. Currently the Ren Lab is actively studying mechanisms of arteriolar differentiation and arteriolar angiogenesis in the cancer progression and Alzheimer’s disease pathogenesis, which may be regulated by an epigenetic and transcriptional signaling pathway as well as CD36-mediated metabolic reprogramming of fatty acids. 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, disease-relevant organoids 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.

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.

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.

6. Adam W. Beck, Herbert Chen and Bin Ren*. Arteriolar angiogenesis: implications in anti-angiogenic immunotherapy for pancreatic cancers, Cytokine and Growth Factor Reviews, Volume 86, December 2025, Pages 96-107. doi: https://doi.org/10.1016/j.cytogfr.2025.10.002 (invited review).