Bronchopulmonary dysplasia (BPD) is a fatal lung disorder that happens when the alveoli of infants stop developing normally. Using mechanical ventilation on infants can cause BPD. The microvessels around the alveoli are also developed in BPD. This study aims to identify different factors important to angiogenesis in infants who have been put on mechanical ventilation. This research team found high levels of Endoglin in the microvessels and low levels of vascular endothelial growth factor and angiopoietin-1 in infants who had been treated with mechanical ventilation.
This study aims to identify different factors important to angiogenesis in infants who have been put on mechanical ventilation or have bronchopulmonary dysplasia (BPD).
Premature newborns who are treated with mechanical ventilation are at high risk for developing bronchopulmonary dysplasia (BPD). The main symptom of BPD is underdeveloped alveoli, which is closely related to the underdeveloped microvessels that are also seen in the disease. The microvessels of BPD infants appear to be immature and have less branching in them compared to infant lungs without BPD. Previous studies have identified vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) as factors that regulate angiogenesis as a baby grows and develops in the womb. Though there is likely a link between VEGF, Ang-1, and BPD, there is conflicting data on how they are all linked.
This study focuses on Endoglin (CD105), which is a protein that allows growth factors to communicate with endothelial cells. Endoglin is usually found on rapidly growing endothelial cells, and is associated with angiogenesis, wound healing, and development.
RNase Protection Assay of Pulmonary Angiogenesis-related Gene Expression
The mRNA of Endoglin was 3 times higher in the short term ventilated infant lungs than the normal lungs. The Endoglin mRNA in long term ventilated lungs was higher overall, but too variable to be a significant finding. VEGF mRNA and Ang-1 mRNA were both lower in the ventilated lungs than in the control lungs.
Western Blot Analysis of Pulmonary Endoglin Expression
The protein expression of isoform L-Endoglin in the ventilated infant lungs was almost 10 times higher than the expression in the normal infant lungs. The isoform S-Endoglin was slightly increased.
Endoglin and PECAM-1 Immunohistochemistry
The group of 23 to 29 weeks of gestation showed that the ventilated infants showed signs of the lung bleeding and emphysema. The ventilated infants had less organized patterns of microvessels around the alveoli than the control group. The Endoglin expression was higher in the ventilated lungs than the control lungs in this assay too.
The group of 30 weeks or more of gestation who had been ventilated long term showed full cases of BPD. The normal lungs showed regular microvessel patterns, while the long term ventilated patients showed underdeveloped capillary patterns. Endoglin expression was weak in the normal lungs of this group, but was highly variable in the ventilated lungs. Overall, the Endoglin expression was higher in the ventilated lungs, but the results were too variable to be significant.
The lungs of infants who have been treated with ventilation have unbranched microvessels surrounding the alveoli, suggesting that the disease can be due to underdeveloped angiogenesis. Because of that, most studies of BPD focus on regulators of angiogenesis VEGF and Ang-1. This study, however, focused on Endoglin and showed that Endoglin may be the cause of the underdeveloped microvessels we see in BPD. Endoglin is essential for healthy angiogenesis. Without any Endoglin, an organism will die before it is born, and organisms heterozygous for Endoglin will live lives with vascular diseases. But, the effects of over-expression of Endoglin on microvessel growth patterns are not well studied. There are two types of Endoglin, called isoforms. L-Endoglin is the dominant form in humans and is thought to increase angiogenesis, where S-Endoglin has been known to decrease angiogenesis. Endoglin has some other functions too that may have caused the underdeveloped microvessel patterns we see with BPD, like Endoglin’s function to regulate the cytoskeleton of cells for example. This function could be causing BPD when Endoglin is overexpressed and not functioning properly. No matter the high number of possible causes for the findings of this study, we now know that Endoglin is upregulated in BPD and can continue with more research accordingly.
This study used RNase Protection assay, Western Blot, and Immunohistochemistry to identify the markers of angiogenesis in the lung tissue and microvessels.
Endoglin may be upregulated for multiple reasons, but can now be associated with BPD in additon to low VEGF and Ang-1 expression. More research should be done to increase the understanding of BPD, infant ventilation, and the factors that affect angiogenesis.