A Pathogenic Relationship of Bronchopulmonary Dysplasia and Retinopathy of Prematurity? A Review of Angiogenic Mediators in Both Diseases

Abstract

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are common and significant morbidities of prematurely born infants. These diseases have in common altered and pathologic vascular formation in the face of incomplete organ development. Therefore, it is reasonable to question whether factors affecting angiogenesis could have a joint pathogenic role for both diseases. Inhibition or induced expression of a single angiogenic factor is unlikely to be 100% causative or protective of either of BPD or ROP. It is more likely that interactions of multiple factors leading to disordered angiogenesis are present, increasing the likelihood of common pathways in both diseases. This review explores this possibility by assessing the evidence showing involvement of specific angiogenic factors in the vascular development and maldevelopment in each disease. Theoretical interactions of specific factors mutually contributing to BPD and ROP are proposed and, where possible, a timeline of the proposed relationships between BPD and ROP is developed. It is hoped that future research will be inspired by the theories put forth in this review to enhance the understanding of the pathogenesis in both diseases.

Keywords: angiogenesis; bronchopulmonary dysplasia; prematurity; retinopathy of prematurity; vasculogenesis.

Figure 1

Proposed clinical timeline depicting the current understanding of BPD and ROP disease development. The data are coordinated with the changes in expression and function of the vascular factors common to BPD and ROP. Using a gestational age of 24 weeks at birth, and current BPD and ROP clinical symptoms and definitions, an infant is determined to have or not have BPD at 36 weeks PMA (approximately 12 weeks of age) but will have clinical signs of developing BPD prior to that time. Phase 1 ROP occurs prior to 31 weeks PMA whereas Phase 2 (development of neovascularization) is believed to occur at 30-32 weeks PMA (6–8 weeks of age for an infant born at 24 weeks gestation). Abbreviations are as documented in text.

Figure 2

Interaction of O₂ with VEGF and eNOS signaling. Oxygen can disrupt VEGF and NO signaling pathways via down regulation of eNOS. Abbreviations are as documented in text.

Figure 3

The regulation of inflammation during lung and retina injury in BPD and ROP. The complex interplay of major factors (PAPP-A, IFNγ, IGF-1, IGFBP-3, and NO) in promoting or reducing inflammation and tissue damage is illustrated, and potential targets for therapeutic intervention are identified. IGFBP-3 upregulates NO in both lung microvascular and hematopoietic stem cells (through PI3K-Akt signaling) and promotes IGF-1 activity, thereby decreasing inflammation and endothelial cell death. In addition to nutritional-induced increased IGFBP-3 levels, the interplay of pathways shown here suggests other points for possible direct therapy. For example, direct inhibition of inflammation and IFNγ may inhibit PAPP-A and release IGF-1 production. Targeting IFN may decrease the expression of Ang2, MMP9, IP-9, and IP-10. Abbreviations are as documented in text.

Figure 4

Ang1 and Ang2 function and regulation. Ang1 and Ang2 control competitive regulatory events in the vascular endothelium. Competitive binding to their common receptor, Tie2, regulates endothelial cell stability and function to inhibit or promote neoangiogenesis, respectively. Ang1 increases endothelial cell survival, tightens intercellular junctions, and increases tyrosine phosphorylation of membrane-bound Tie2. Ang2 decreases endothelial cell stability, increases vascular sprouting and leakage, and decreases tyrosine phosphorylation of Tie2, promoting angiogenesis. The resulting competitive signals combine to stabilize formed vessels, allowing them to mature, and simultaneously maintain neovascularization as dictated by tissue oxygen needs. The amounts of free Ang1 and Ang2 available for binding Tie2 are modulated by soluble Tie2 (sTie2), which is formed by proteolytic cleavage and release of the extracellular component of the membrane bound Tie 2 receptor. Circulating sTie2 binds both Ang1 and Ang2, making them unavailable for binding Tie2 to influence endothelial cell functions. Because sTie2 has a higher affinity for Ang1 than Ang 2 the amount of sTie2 exerts differential control of Ang1 and Ang2 effects. Increased levels of sTie2 favor an overall increase in new vessel sprouting because more Ang1 than Ang2 is bound up. Abbreviations are as documented in text.