Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

Pediatr Res. 2019 May;85(6):754-768. doi: 10.1038/s41390-019-0345-4. Epub 2019 Feb 19.

Abstract

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is characterized by pulmonary hypoplasia and pulmonary hypertension (PHTN). PHTN secondary to CDH is a result of vascular remodeling, a structural alteration in the pulmonary vessel wall that occurs in the fetus. Factors involved in vascular remodeling have been reported in several studies, but their interactions remain unclear. To help understand PHTN pathophysiology and design novel preventative and treatment strategies, we have conducted a systematic review of the literature and comprehensively analyzed all factors and pathways involved in the pathogenesis of pulmonary vascular remodeling secondary to CDH in the nitrofen model. Moreover, we have linked the dysregulated factors with pathways involved in human CDH. Of the 358 full-text articles screened, 75 studies reported factors that play a critical role in vascular remodeling secondary to CDH. Overall, the impairment of epithelial homeostasis present in pulmonary hypoplasia results in altered signaling to endothelial cells, leading to endothelial dysfunction. This causes an impairment of the crosstalk between endothelial cells and pulmonary artery smooth muscle cells, resulting in increased smooth muscle cell proliferation, resistance to apoptosis, and vasoconstriction, which clinically translate into PHTN.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Endothelial Cells / physiology
  • Female
  • Hernias, Diaphragmatic, Congenital / complications*
  • Hernias, Diaphragmatic, Congenital / pathology
  • Hernias, Diaphragmatic, Congenital / physiopathology
  • Humans
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Infant, Newborn
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / pathology
  • Myocytes, Smooth Muscle / physiology
  • Phenyl Ethers / toxicity
  • Pregnancy
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / pathology
  • Pulmonary Artery / physiopathology
  • Rats
  • Risk Factors
  • Vascular Remodeling / drug effects
  • Vascular Remodeling / physiology

Substances

  • Phenyl Ethers
  • nitrofen

Grants and funding