Alveolar capillary dysplasia (ACD) is a rare lung developmental disorder leading to persistent pulmonary arterial hypertension and fatal outcomes in newborns. In this study, we 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 control 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, hypoxia-inducible factor 1α (HIF1A), and angiopoietin signaling pathways compared with pulmonary arterial hypertension/healthy controls. Histologically, there was a markedly increased prevalence of TEK receptor tyrosine kinase (TIE)(+) macrophages in ACD, compared with the other groups, whereas CXCL12 and HIF1A showed high expression in all groups. ACD is characterized by dysfunctional capillaries and a high prevalence of intussusceptive angiogenesis. Endothelial C-X-C motif chemokine receptor 4, HIF1A, and angiopoietin signaling as well as TIE2(+) macrophages appear 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.
- Kamp, J. C.
- Neubert, L.
- Ackermann, M.
- Stark, H.
- Plucinski, E.
- Shah, H. R.
- Janciauskiene, S.
- Bergmann, A. K.
- Schmidt, G.
- Welte, T.
- Haverich, A.
- Werlein, C.
- Braubach, P.
- Laenger, F.
- Schwerk, N.
- Olsson, K. M.
- Fuge, J.
- Park, D. H.
- Schupp, J. C.
- Hoeper, M. M.
- Kuehnel, M.
- Jonigk, D. D.
