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A Morphomolecular Approach to Alveolar Capillary Dysplasia
Jan C Kamp1, Lavinia Neubert2, Maximilian Ackermann3
1Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany.
The American Journal of Pathology
|June 1, 2022
Summary
Alveolar capillary dysplasia (ACD) involves abnormal lung capillaries and increased intussusceptive angiogenesis. Key pathways like CXCR4 and HIF1A, along with TIE2+ macrophages, drive this vascular remodeling in newborns.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Vascular Biology
Background:
- Alveolar capillary dysplasia (ACD) is a rare, fatal neonatal lung disorder causing persistent pulmonary hypertension.
- Understanding ACD's microvascular and molecular basis is critical for identifying therapeutic targets.
Purpose of the Study:
- To analyze the microvascular morphology and molecular pathways in Alveolar capillary dysplasia (ACD).
- To identify key cellular and molecular players involved in ACD-related vascular remodeling.
Main Methods:
- Exome sequencing and array-based comparative genomic hybridization on ACD samples.
- Scanning electron microscopy of microvascular corrosion casts to assess vascular morphology.
- Gene expression, pathway analysis, and immunostaining for protein expression.
Main Results:
- ACD lungs exhibit an altered capillary network with a high prevalence of intussusceptive angiogenesis.
- Increased activity of C-X-C motif chemokine receptor 4 (CXCR4), hypoxia-inducible factor 1α (HIF1A), and angiopoietin signaling pathways were observed in ACD.
- A marked increase in endothelial tyrosine kinase receptor (TEK/TIE2)+ macrophages was found in ACD compared to controls.
Conclusions:
- ACD is characterized by dysfunctional capillaries and significant intussusceptive angiogenesis.
- Endothelial CXCR4, HIF1A, angiopoietin signaling, and TIE2+ macrophages are crucial for ACD's vascular remodeling.
- Targeting TIE2 may offer a therapeutic strategy for Alveolar capillary dysplasia.
