title: Isolation and characterization of human esophageal microvascular endothelial cells: mechanisms of inflammatory activation.
abstract: Gastroesophageal reflux disease is the most common malady of the esophagus, affecting 7% of the United States population. Histological assessment demonstrates classic inflammatory mechanisms including selective leukocyte recruitment and hemorrhage, suggesting a prominent role for the microvasculature. We isolated and characterized human esophageal microvascular endothelial cells (EC) (HEMEC), examined inflammatory activation in response to cytokines, LPS, and acidic pH exposure, and identified signaling pathways that underlie activation. HEMEC displayed characteristic morphological and phenotypic features including acetylated LDL uptake. TNF-alpha/LPS activation of HEMEC resulted in upregulation of the cell adhesion molecules (CAM) ICAM-1, VCAM-1, E-selectin, and mucosal addressin CAM-1 (MAdCAM-1), increased IL-8 production, and enhanced leukocyte binding. Both acid and TNF-alpha/LPS activation lead to activation of SAPK/JNK in HEMEC that was linked to VCAM-1 expression and U-937 leukocyte adhesion. Expression of constitutive inducible nitric oxide synthase in HEMEC was in marked contrast to intestinal microvascular endothelial cells. In this study, we demonstrate that HEMECs are phenotypically and functionally distinct from lower gut-derived endothelial cells and will facilitate understanding of inflammatory mechanisms in esophageal inflammation.
authors.affiliation: Department of Surgery, Division of Gastroenterology and Hepatology, Medical College of Wisconsin Dysphagia Institute, Milwaukee 53226, USA.
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Rafiee
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ogawa
authors.forename: Jan
authors.initials: J
authors.lastname: Heidemann
authors.forename: Mona S
authors.initials: MS
authors.lastname: Li
authors.forename: Mohammed
authors.initials: M
authors.lastname: Aslam
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lamirand
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Fisher
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Graewin
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Johnson
authors.forename: Reza
authors.initials: R
authors.lastname: Shaker
authors.forename: David G
authors.initials: DG
authors.lastname: Binion
mesh_terms: D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004941:Esophagitis / Q000209:etiology; D004947:Esophagus / Q000098:blood supply*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007422:Intestines / Q000098:blood supply; D048031:JNK Mitogen-Activated Protein Kinases; D007962:Leukocytes / Q000502:physiology; D008833:Microcirculation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009088:Mucoproteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010641:Phenotype; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D003474:Curcumin