ABSTRACT
The cellular mechanisms underlying the microvascular dysangiogenesis of bronchopulmonary dysplasia (chronic lung disease of the newborn) remain largely undetermined. We report unusual pulmonary vascular findings in a 27-week-gestation male newborn who died on the second day of life from intractable respiratory failure, following a pregnancy complicated by prolonged membrane rupture and persistent severe oligohydramnios. As expected, postmortem examination revealed pulmonary hypoplasia (lung/body weight ratio: 2.23%; 10th percentile for 27 weeks: 2.59%). In addition, lung microscopy revealed complex networks of non-sprouting, tortuous, and bulbously dilated capillaries, randomly distributed in widened airspace septa. Anti-smooth muscle actin immunohistochemistry demonstrated immunoreactive central densities within capillary lumina, suggestive of intravascular pillar formation. The plexus-forming, non-sprouting type of angiogenesis and apparent transluminal pillar formation are consistent with intussusceptive ("longitudinal splitting") angiogenesis. In concordance with previous observations made in human fetal lung xenografts, these findings support the notion that human postcanalicular lungs have the capacity to switch from sprouting to non-sprouting, intussusceptive-like angiogenesis, possibly representing an adaptive response activated by hemodynamic flow alterations and/or hypoxia. The possible relationship between the intussusceptive-like vascular changes observed in this case and the microvascular dysangiogenesis characteristic of bronchopulmonary dysplasia remains to be determined.
Subject(s)
Infant, Premature, Diseases/diagnosis , Lung Diseases/diagnosis , Lung Diseases/pathology , Lung/blood supply , Neovascularization, Pathologic/diagnosis , Vascular Diseases/diagnosis , Vascular Diseases/pathology , Fatal Outcome , Humans , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/pathology , Lung/pathology , Lung Diseases/congenital , Male , Neovascularization, Pathologic/congenital , Neovascularization, Pathologic/pathology , Vascular Diseases/congenitalABSTRACT
In addition to its vasodilator properties, nitric oxide (NO) promotes angiogenesis in the systemic circulation and tumors. However, the role of NO in promoting normal lung vascular growth and its impact on alveolarization during development or in response to perinatal stress is unknown. We hypothesized that NO modulates lung vascular and alveolar growth and that decreased NO production impairs distal lung growth in response to mild hypoxia. Litters of 1-day-old mouse pups from parents that were heterozygous for endothelial nitric oxide synthase (eNOS) deficiency were placed in a hypobaric chamber at a simulated altitude of 12,300 ft (Fi(O(2)) = 0.16). After 10 days, the mice were killed, and lungs were fixed for morphometric and molecular analysis. Compared with wild-type controls, mean linear intercept (MLI), which is inversely proportional to alveolar surface area, was increased in the eNOS-deficient (eNOS -/-) mice [51 +/- 2 micro m (eNOS -/-) vs. 41 +/- 1 micro m (wild type); P < 0.01]. MLI was also increased in the eNOS heterozygote (+/-) mice (44 +/- 1 micro m; P < 0.03 vs. wild type). Vascular volume density was decreased in the eNOS -/- mice compared with wild-type controls (P < 0.03). Lung vascular endothelial growth factor (VEGF) protein and VEGF receptor-1 (VEGFR-1) protein content were not different between the study groups. In contrast, lung VEGFR-2 protein content was decreased from control values by 63 and 34% in the eNOS -/- and eNOS +/- mice, respectively (P < 0.03). We conclude that exposure to mild hypoxia during a critical period of lung development impairs alveolarization and reduces vessel density in the eNOS-deficient mouse. We speculate that NO preserves normal distal lung growth during hypoxic stress, perhaps through preservation of VEGFR-2 signaling.
Subject(s)
Hypoxia/metabolism , Nitric Oxide Synthase/genetics , Pulmonary Alveoli/abnormalities , Pulmonary Alveoli/metabolism , Animals , Animals, Newborn , Body Weight , Endothelial Growth Factors/biosynthesis , Hernia, Diaphragmatic/metabolism , Hernia, Diaphragmatic/pathology , Hernias, Diaphragmatic, Congenital , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Intercellular Signaling Peptides and Proteins/biosynthesis , Lymphokines/biosynthesis , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Neovascularization, Pathologic/congenital , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Oxygen/pharmacology , Phenotype , Pulmonary Alveoli/pathology , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor Receptor-1/biosynthesis , Vascular Endothelial Growth Factor Receptor-2/biosynthesis , Vascular Endothelial Growth FactorsABSTRACT
At autopsy we examined eight eyes of six infants with Potter's syndrome, an idiopathic multisystem condition with a constellation of ocular anomalies, to explore its ocular component more fully and systematically. A striking abnormality in some cases was the presence of dilated intraocular blood vessels, and these were sometimes associated with retinal and preretinal neovascularization reminiscent of the vasoproliferative stage of retrolental fibroplasia. Since oxygen therapy cannot be implicated in these cases, other causes, either genetic or environmental, must be sought. The presence of nonretinal ocular vascular anomalies, such as iris capillary dilation, peripapillary angioma formation, and vascular anomalies in nonocular tissue, point to a generalized derangement in the control of ocular angiogenesis. Our study indicated that an understanding of the pathogenesis of the vascular anomalies in Potter's syndrome is clearly relevant to other more common retinopathies that are associated with neovascularization.
