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Citation
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HERO ID
2272056
Reference Type
Journal Article
Title
The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models
Author(s)
Dickinson, MG; Bartelds, B; Borgdorff, MAJ; Berger, RMF
Year
2013
Is Peer Reviewed?
Yes
Journal
American Journal of Physiology: Lung Cellular and Molecular Physiology
ISSN:
1040-0605
EISSN:
1522-1504
Volume
305
Issue
1
Page Numbers
L1-L14
PMID
23624788
DOI
10.1152/ajplung.00031.2013
Web of Science Id
WOS:000321187900001
Abstract
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e., systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression. PAH animal models are important for obtaining insight in new pathobiological processes and therapeutical targets. However, as for any preclinical model the pathophysiological mechanism and clinical course has to be comparable to the human disease that it mimics. This means that animal models mimicking human PAH ideally are characterized by: a hit recognized in human disease (e.g., altered pulmonary blood flow), specific vascular remodeling resembling human neointimal lesions, and disease progression that leads to right ventriclular dysfunction and death. A review that underlines the current knowledge of PAH due to disturbed flow is still lacking. In this review we will summarize the current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow and address questions for future treatment strategies for PAH.
Keywords
congenital heart diseases; pulmonary vascular remodeling; neointimal lesions; endothelial cells; smooth muscle cells; proliferation
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