Thrombus leukocytes exhibit more endothelial cell-specific angiogenic markers than peripheral blood leukocytes do in acute coronary syndrome patients, suggesting a possibility of trans-differentiation: a comprehensive database mining study.
Current angiogenic therapies for cancers and cardiovascular diseases have not yet achieved expected benefits, which reflects the need for improved understanding of angiogenesis. In this study, we focused on solving the problem of whether tissues have different angiogenic potentials (APs) in physiological conditions and how angiogenesis is regulated in various disease conditions.



In healthy and diseased human and mouse tissues, we profiled the expression of 163 angiogenic genes, including transcription regulators (TRs), growth factors and receptors (GF/Rs), cytokines and chemokines (C/Cs), and proteases and inhibitors (P/Is). TRs were categorized as inflammatory, homeostatic, and endothelial cell-specific TRs, and C/Cs were categorized as pro-angiogenic, anti-angiogenic, and bi-functional C/Cs.



We made the following findings: (1) the human heart, muscle, eye, pancreas, and lymph node are among the tissues with the highest APs; (2) tissues with high APs have more active angiogenic pathways and angiogenic C/C responses; (3) inflammatory TRs dominate regulation of all angiogenic C/Cs; homeostatic TRs regulate all to a lower extent, while endothelial cell-specific TRs mainly regulate pro-angiogenic and bi-functional C/Cs; (4) tissue AP is positively correlated with the expression of oxygen sensors PHD2 and HIF1B, VEGF pathway gene VEGFB, and stem cell gene SOX2; (5) cancers of the digestive system tend to have increased angiogenesis dominated by endothelial cell-specific pro-angiogenic pathways, while lung cancer and prostate cancer have significantly decreased angiogenesis; and (6) endothelial cell-specific pro-angiogenic pathways are significantly increased in thrombus-derived leukocytes in patients with acute coronary artery disease.



Our results demonstrate that thrombus-derived leukocytes express more endothelial cell-specific angiogenic markers to directly promote angiogenesis after myocardial infarction and that certain solid tumors may be more sensitive to anti-angiogenic therapies than others.
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Hangfei
H
Fu
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Nish
N
Vadalia
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Eric R
ER
Xue
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Candice
C
Johnson
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Department of Cardiovascular Medicine, The Second Affiliated Hospital at Nanchang University, Nanchang, Jiangxi, 330006, China.
Luqiao
L
Wang
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
William Y
WY
Yang
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Claudette
C
Sanchez
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Jun
J
Nelson
Department of Physiology, University of Oklahoma College of Medicine, Oklahoma City, OK, 73104, USA.
Qian
Q
Chen
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Department of Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Eric T
ET
Choi
Department of Physiology, University of Oklahoma College of Medicine, Oklahoma City, OK, 73104, USA.
Jian-Xing
JX
Ma
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Jun
J
Yu
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Hong
H
Wang
Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA. xfyang@temple.edu.|Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA. xfyang@temple.edu.|Center for Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, 10th Floor, Philadelphia, PA, 19140, USA. xfyang@temple.edu.|Center for Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA. xfyang@temple.edu.
Xiaofeng
0000-0002-6854-6195
X
Yang
D054058:Acute Coronary Syndrome / Q000503:physiopathology*; D042501:Angiogenic Proteins / Q000235:genetics; D000818:Animals; D015415:Biomarkers; D054338:Cell Transdifferentiation; D057225:Data Mining; D042783:Endothelial Cells; D006801:Humans; D007962:Leukocytes / Q000473:pathology*; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology; D009369:Neoplasms / Q000098:blood supply / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D018919:Neovascularization, Physiologic; D013927:Thrombosis / Q000473:pathology*; D059467:Transcriptome
D042501:Angiogenic Proteins; D015415:Biomarkers
Angiogenic genes; Angiogenic leukocytes; Immune regulation of angiogenesis; Pathological modulation of angiogenesis; Tissue expression of genes