Comprehensive three‐dimensional morphology of neoangiogenesis in pulmonary veno‐occlusive disease and pulmonary capillary hemangiomatosis

Pulmonary veno‐occlusive disease (PVOD) is a rare lung disease characterized by fibrotic narrowing of pulmonary veins leading to pulmonary hypertension (PH) and finally to death by right heart failure. PVOD is often accompanied by pulmonary capillary hemangiomatosis (PCH), a marked abnormal proliferation of pulmonary capillaries. Both morphological patterns often occur together and are thought to be distinct manifestations of the same disease process and accordingly are classified together in group 1′ of the Nice classification of PH. The underlying mechanisms of these aberrant remodeling processes remain poorly understood. In this study, we investigated the three‐dimensional structure of these vascular lesions in the lung explant of a patient diagnosed with PVOD by μ‐computed tomography, microvascular corrosion casting, electron microscopy, immunohistochemistry, correlative light microscopy and gene expression analysis. We were able to describe multifocal intussusceptive neoangiogenesis and vascular sprouting as the three‐dimensional correlate of progressive PCH, a process dividing pre‐existing vessels by intravascular pillar formation previously only known from embryogenesis and tumor neoangiogenesis. Our findings suggest that venous occlusions in PVOD increase shear and stretching forces in the pulmonary capillary bloodstream and thereby induce intussusceptive neoangiogenesis. These findings can serve as a basis for novel approaches to the analysis of PVOD.

[1]  F. Länger,et al.  Schädigungsmuster interstitieller Lungenerkrankungen , 2018, Der Pathologe.

[2]  A. Gaumann,et al.  Plexiform Vasculopathy in Chronic Thromboembolic Pulmonary Hypertension. , 2017, American journal of respiratory and critical care medicine.

[3]  M. Humbert,et al.  Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study. , 2017, The Lancet. Respiratory medicine.

[4]  T. Lincoln,et al.  Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and -independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency. , 2016, American journal of physiology. Heart and circulatory physiology.

[5]  Simon Gibbs,et al.  2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension , 2015, European Respiratory Journal.

[6]  M. Konerding,et al.  Intussusceptive angiogenesis: expansion and remodeling of microvascular networks , 2014, Angiogenesis.

[7]  J. Haefliger,et al.  The use of external mesh reinforcement to reduce intimal hyperplasia and preserve the structure of human saphenous veins. , 2014, Biomaterials.

[8]  M. Humbert,et al.  EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension , 2013, Nature Genetics.

[9]  H. Baldwin,et al.  Role of Tie1 in shear stress and atherosclerosis. , 2011, Trends in cardiovascular medicine.

[10]  Y. Sasaguri,et al.  Pulmonary capillary hemangiomatosis in chronic cardiac failure due to aortic stenosis. , 2009, Journal of UOEH.

[11]  A. Nicholson,et al.  Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis: A Clinicopathologic Study of 35 Cases , 2006, The American journal of surgical pathology.

[12]  J. Rouleau,et al.  Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. , 1988, Annals of internal medicine.

[13]  R. Bhadra,et al.  NIH Public Access , 2014 .

[14]  Ye Zeng,et al.  CXCR1 and CXCR2 are novel mechano-sensors mediating laminar shear stress-induced endothelial cell migration. , 2011, Cytokine.