title: The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models.
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.
authors.affiliation: Center for Congenital Heart Diseases, Division of Pediatric Cardiology Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. m.g.dickinson@umcg.nl
authors.forename: Michael G
authors.initials: MG
authors.lastname: Dickinson
authors.forename: Beatrijs
authors.initials: B
authors.lastname: Bartelds
authors.forename: Marinus A J
authors.initials: MA
authors.lastname: Borgdorff
authors.forename: Rolf M F
authors.initials: RM
authors.lastname: Berger
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology*; D012039:Regional Blood Flow / Q000502:physiology*
keywords: congenital heart diseases; endothelial cells; neointimal lesions; proliferation; pulmonary vascular remodeling; smooth muscle cells