1. Egr-1 Expression During Neointimal Development in Flow-Associated Pulmonary Hypertension
- Author
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Hannie Sietsma, Beatrijs Bartelds, Pieter Wichers, Michel Weij, Janny Takens, Bibiche Boersma, Grietje Molema, Rolf M. F. Berger, Michael G. Dickinson, Marinus A.J. Borgdorff, Faculteit Medische Wetenschappen/UMCG, Nanotechnology and Biophysics in Medicine (NANOBIOMED), Cardiovascular Centre (CVC), Vascular Ageing Programme (VAP), Groningen Kidney Center (GKC), and Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE)
- Subjects
Heart Defects, Congenital ,Neointima ,Pathology ,medicine.medical_specialty ,Hypertension, Pulmonary ,Hemodynamics ,Biology ,Real-Time Polymerase Chain Reaction ,GROWTH-FACTOR EXPRESSION ,Pathology and Forensic Medicine ,Muscle hypertrophy ,FLUID SHEAR-STRESS ,Arteriovenous Shunt, Surgical ,medicine ,INJURY ,Animals ,Humans ,Familial Primary Pulmonary Hypertension ,Rats, Wistar ,Early Growth Response Protein 1 ,Laser capture microdissection ,GENE-EXPRESSION ,TARGETING EGR-1 ,Monocrotaline ,Vascular disease ,PROLIFERATION ,Regular Article ,VASCULAR-DISEASE ,IN-VITRO ,medicine.disease ,Immunohistochemistry ,Pulmonary hypertension ,Rats ,Repressor Proteins ,body regions ,Real-time polymerase chain reaction ,MUSCLE-CELL GROWTH ,ARTERIAL-HYPERTENSION ,Blood Flow Velocity ,hormones, hormone substitutes, and hormone antagonists - Abstract
In flow-associated pulmonary arterial hypertension (PAH), increased pulmonary blood flow is an essential trigger for neointimal formation. Using microarray analysis, we recently found that the early growth response protein 1 (Egr-1) transcription factor is increased in experimental flow-associated end-stage PAH. Its role in PAH development is unknown. Here, we assessed the spatiotemporal expression of Egr-1 during neointimal development in flow-associated PAH. Flow-associated PAH was produced in rats by combining monocrotaline administration with an aortocaval shunt. Animals were sacrificed 1 day before or 1 day, 1 week, or 4 to 5 weeks after flow addition. Egr-1 expression was spatiotemporally assessed using laser microdissection, quantitative real-time PCR and immunohistochemistry. In addition, Egr-1 expression was assessed in a non-neointimal pulmonary hypertension model and in human PAH associated with congenital shunt. In 4 to 5 weeks, rats subjected to increased flow developed PAH with neointimal lesions. Egr-1 mRNA was increased 1 day after flow addition and in end-stage PM!, whereas monocrotaline only did not result in increased Egr-1 mRNA. Directly after flow addition, Egr-1 was expressed in endothelial cells. During disease development, Egr-1 protein expression increased and migrated throughout the vessel wall. In PM! patients, Egr-1 was expressed in vessels with media hypertrophy and neointimal lesions, including plexiform lesions. Thus, Egr-1 may be an important regulator in the development of pulmonary neointimal lesions induced by increased pulmonary blood flow. (Am J Pathol 2011, 179:2199-2209; DOI: 10.1016/j.ajpath.2011.07.030)
- Published
- 2011