title: Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats.
abstract: Peripheral ischemia, resulting from diminished arterial flow and defective local vascularization, is one of the main causes of impaired wound healing in diabetes. Vasodilatory prostaglandins (PGs), including PGE2 and PGI2, regulate blood flow in peripheral tissues. PGs also stimulate angiogenesis by inducing vascular endothelial growth factor. However, PG levels are reduced in diabetes mainly due to enhanced degradation. We hypothesized that inhibition of the prostaglandin transporter (PGT) (SLCO2A1), which mediates the degradation of PGs, would increase blood flow and stimulate vascularization, thereby mitigating peripheral ischemia and accelerating wound healing in diabetes. Here we report that inhibiting PGT with intravenously injected PGT inhibitor, T26A, increased blood flow in ischemic hind limbs created in non-diabetic rats and streptozotocin induced diabetic rats. Systemic, or combined with topical, T26A accelerated closure of cutaneous wounds. Immunohistochemical examination revealed that inhibition of PGT enhanced vascularization (marked by larger numbers of vessels formed by CD34+ cells), and accelerated re-epithelialization of cutaneous wounds. In cultured primary human bone marrow CD34+ cells and human epidermal keratinocytes (HEKs) either inhibiting or silencing PGT increased migration in both cell lines. Thus PGT directly regulates mobilization of endothelial progenitor cells (EPCs) and HEKs, which could contribute to PGT-mediated vascularization and re-epithelialization. At the molecular level, systemic inhibition of PGT raised circulating PGE2. Taken together, our data demonstrate that PGT modulates arterial blood flow, mobilization of EPCs and HEKs, and vascularization and epithelialization in wound healing by regulating vasodilatory and pro-angiogenic PGs.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY, United States of America.
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY, United States of America.
authors.forename: Outhiriaradjou
authors.initials: O
authors.lastname: Benard
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY, United States of America.
authors.forename: Mahrukh M
authors.initials: MM
authors.lastname: Syeda
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY, United States of America; Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, NY, United States of America.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Schuster
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY, United States of America.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chi
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D062326:Re-Epithelialization / Q000187:drug effects / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; C569290:N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4-((4-((2-(2-(2-benzamidoethoxy)ethoxy)ethyl)amino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)benzamide; D027361:Organic Anion Transporters; D011453:Prostaglandins; C503528:Slco2a1 protein, rat; D014227:Triazines; D062366:para-Aminobenzoates; D013311:Streptozocin