Jan C. Kamp, Lavinia Neubert, Maxmilian Ackermann, Helge Stark, Edith Plucinski, Harshit R. Shah, Sabina Janciauskiene, Anke K. Bergmann, Gunnar Schmidt, Tobias Welte, Axel Haverich, Christopher Werlein, Peter Braubach, Florian Laenger, Nicolaus Schwerk, Karen M. Olsson, Jan Fuge, Da-Hee Park, Jonas C. Schupp, Marius M. Hoeper, Mark P. Kuehnel, Danny D. Jonigk
Hannover Medical School. University Medical Center of the Johannes Gutenberg-University Mainz.
Germany
American Journal of Pathology
Am J Pathol 2022; 192: 1110-1121
DOI: 10.1016/j.ajpath.2022.05.004
Abstract
Alveolar capillary dysplasia (ACD) is a rare lung developmental disorder leading to persistent pulmonary arterial hypertension and fatal outcomes in newborns. The current study analyzed the microvascular morphology and the underlying molecular background of ACD. One ACD group (n = 7), one pulmonary arterial hypertension group (n = 20), and one healthy con1trol group (n = 16) were generated. Samples of histologically confirmed ACD were examined by exome sequencing and array-based comparative genomic hybridization. Vascular morphology was analyzed using scanning electron microscopy of microvascular corrosion casts. Gene expression and biological pathways were analyzed using two panels on inflammation/kinase-specific genes and a comparison analysis tool. Compartment-specific protein expression was analyzed using immunostaining. In ACD, there was an altered capillary network, a high prevalence of intussusceptive angiogenesis, and increased activity of C-X-C motif chemokine receptor 4 (CXCR4), hypoxia-inducible factor 1α (HIF1A), and angiopoietin signaling pathways compared with pulmonary arterial hypertension/healthy controls. Histologically, there was a markedly increased prevalence of endothelial tyrosine kinase receptor (TEK/TIE2)+ macrophages in ACD, compared with the other groups, whereas the CXCR4 ligand CXCL12 and HIF1A showed high expression in all groups. ACD is characterized by dysfunctional capillaries and a high prevalence of intussusceptive angiogenesis. The results indicate that endothelial CXCR4, HIF1A, and angiopoietin signaling as well as TIE2+ macrophages are crucial for the induction of intussusceptive angiogenesis and vascular remodeling. Future studies should address the use of anti-angiogenic agents in ACD, where TIE2 appears as a promising target.
Category
Class III. Developmental Diseases of the Lung
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes