A Morphomolecular Approach to Alveolar Capillary Dysplasia

Alveolar capillary dysplasia (ACD) is a rare lung developmental disorder leading to persistent pul-monary 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 elec-tron 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 1a (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) thorn 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 thorn macrophages are crucial for the induction of intussus-ceptive angiogenesis and vascular remodeling. Future studies should address the use of anti-angiogenic agents in ACD, where TIE2 appears as a promising target. (Am J Pathol 2022, 192: 1110-1121; https://doi.org/10.1016/j.ajpath.2022.05.004)

Automated summary

This study analyzed the microvascular morphology and molecular background of ACD, revealing characteristics such as altered capillary network, high prevalence of intussusceptive angiogenesis, and increased activity of key signaling pathways in ACD patients.