Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions

Abstract

expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions. Am J Physiol Lung Cell Mol Physiol 298: L483-L491, 2010. First published December 18, 2009 doi:10.1152/ajplung.00106.2009.-Pulmonary arterial hypertension (PAH) is a pulmonary angioproliferative disease with high morbidity and mortality, characterized by a typical pattern of pulmonary vascular remodeling including neointimal lesions. In congenital heart disease, increased pulmonary blood flow has appeared to be a key mediator in the development of these characteristic lesions, but the molecular mechanisms underlying the pulmonary vascular lesions are largely unknown. We employed a rat model of flow-associated PAH, which induced specific pulmonary neointimal lesions. We identified gene expression profiles in rats specifically related to the addition of increased pulmonary blood flow to monocrotaline and the associated occurrence of neointimal lesions. Increased pulmonary blood flow induced the expression of the transcription factors activating transcription factor-3 (ATF3) and early growth response factor-1 (EGR-1), for which presence was confirmed in neointimal lesions. Monocrotaline alone induced increased numbers of activated mast cells and their products. We further identified molecular pathways that may be involved in treatment with the prostacyclin analog iloprost, a vasoactive compound with clinically beneficial effects in patients with PAH, which were similar to pathways described in samples from patient studies. These pathways, associated with the development of angioproliferative lesions as well as with the response to therapy in PAH, may provide new therapeutic targets.remodeling; congenital heart defects PULMONARY ARTERIAL HYPERTENSION (PAH) is a progressive angioproliferative disease with high morbidity and mortality (4), associated with a characteristic pattern of vascular remodeling of the small pulmonary arteries. This vascular remodeling consists of proliferation of endothelial and smooth muscle cells, fibrosis, and inflammation, leading to formation of concentric neointimal lesions and plexiform lesions (37). These latter vascular lesions can be regarded as pathognomonic for PAH (37). Although the histopathology is well-described, the pathogenesis of the disease and its typical vascular lesions is largely unknown (28). In patients with congenital heart diseases that develop PAH, increased pulmonary blood flow has been clinically identified as a key mediator in the development of the pathognomonic vascular lesions of PAH (10, 33, 37) and through unknown mechanisms.Prostacyclin, a vascular endothelium-derived vasoactive compound with vasodilatory and antiproliferative properties, is believed to interfere with the pathogenesis, since prostacyclin analogs have been demonstrated to have beneficial clinical effects in patients with PAH (3, 30). These analogs have been suggested to be able to reverse the pulmonary vascular remodeling process of pulmonary hypertension (PH) in experimental settings (31), altho...

Egr-1 Expression During Neointimal Development in Flow-Associated Pulmonary Hypertension

“…7,8 Rats were anesthetized with 3% to 5% isoflurane inhalation. A fluid-filled pressure catheter was inserted into the right internal jugular vein and guided to the pulmonary artery under pressure waveform monitoring using a bedside monitor.…”

“…7,8,18 Intra-acinar vessels without a clearly defined internal lamina elastica combined with luminal occlusion were defined as neointimal lesions. Intra-acinar vessels with a double lamina elastica for more than half of its circumference were defined as completely muscular.…”

“…We and other investigators have shown that combining monocrotaline with an increased pulmonary blood flow results in pulmonary neointimal lesions in end-stage disease. [7][8][9][10] Little is known about the development of these lesions during disease progression.In a rat model of flow-associated PAH, we recently identified the early growth response protein 1 (Egr-1) transcription factor, by microarray analysis, to be upregulated in end-stage PAH only when increased pulmonary blood flow was added to monocrotaline administration. 8 Egr-1 is expressed in a variety of cardiovascular…”

“…We and other investigators have shown that combining monocrotaline with an increased pulmonary blood flow results in pulmonary neointimal lesions in end-stage disease. [7][8][9][10] Little is known about the development of these lesions during disease progression.…”

“…8 Egr-1 is expressed in a variety of cardiovascular Accepted for publication July 26, 2011. Supplemental material for this article can be found at http://ajp. amjpathol.org or at doi: 10.1016/j.ajpath.2011.07.…”