Abstract
Retinopathy of prematurity (ROP) is a blinding aberrancy of retinal vascular maturation in preterm infants. Despite delayed onset after preterm birth, representing a window for therapeutic intervention, we cannot prevent or cure ROP blindness. A natural form of ROP protection exists in the setting of early-onset maternal preeclampsia, though is not well characterized. As ischemia is a central feature in both ROP and preeclampsia, we hypothesized that angiogenesis mediators may underlie this protection. To test our hypothesis we analyzed peripheral blood expression of candidate proteins with suggested roles in preeclamptic and ROP pathophysiology and with a proposed angiogenesis function (HTRA-1, IGF-1, TGFβ-1, and VEGF-A). Analysis in a discovery cohort of 40 maternal-infant pairs found that elevated HTRA-1 (high-temperature requirement-A serine peptidase-1) was significantly associated with increased risk of ROP and the absence of preeclampsia, thus fitting a model of preeclampsia-mediated ROP protection. We validated these findings and further demonstrated a dose-response between systemic infant HTRA-1 expression and risk for ROP development in a larger and more diverse validation cohort consisting of preterm infants recruited from two institutions. Functional analysis in the oxygen-induced retinopathy (OIR) murine model of ROP supported our systemic human findings at the local tissue level, demonstrating that HtrA-1 expression is elevated in both the neurosensory retina and retinal pigment epithelium by RT-PCR in the ROP disease state. Finally, transgenic mice over-expressing HtrA-1 demonstrate greater ROP disease severity in this model. Thus, HTRA-1 may underlie ROP protection in preeclampsia and represent an avenue for disease prevention, which does not currently exist.
Highlights
Retinopathy of prematurity (ROP) represents a significant risk of childhood blindness and demonstrates increasing incidence with improved survival of low birth-weight infants (Binenbaum et al, 2012; Quinn, 2016)
Expression of each candidate protein was measured in maternal or infant plasma using either ELISA [HTRA-1 (LSBio #LSF11673), IGF-1 (R&D #DG-100)] or Luminex (TGFβ-1 and VEGF-A) when a clinical test was available through the ARUP clinical laboratory (ARUP Laboratories, 2020 | ARUP Laboratories, n.d.)
The ability of potential predictive factors to discriminate between patients with and without ROP was assessed in terms of area under the receiver operating characteristic curve (AUC), with confidence intervals and p-values computed via 10,000 patient-wise bootstrap samples
Summary
Retinopathy of prematurity (ROP) represents a significant risk of childhood blindness and demonstrates increasing incidence with improved survival of low birth-weight infants (Binenbaum et al, 2012; Quinn, 2016). While the molecular basis for observed ROP protection is not clear, this relationship has considerable support in the literature, including in a recent systematic review and meta-analysis (Fortes et al, 2011; Yu et al, 2012; Yau et al, 2015, 2016; Shulman et al, 2017; Azami et al, 2018; Morsing et al, 2018; Razak et al, 2018; Marins et al, 2019) This protective relationship is substantiated in animal models of preeclamptic and ROP disease (Fung et al, 2011; Becker et al, 2017). As ischemia is a central feature in both ROP and preeclampsia, we further hypothesized that angiogenesis mediators play a role in the observed ROP protection To test this hypothesis we adopted a candidate approach, analyzing the systemic expression of proteins suggested to play a role in either preeclamptic or ROP pathophysiology and with a direct or indirect function in angiogenesis. We further validate our findings through multiple lines of evidence in animal models to better understand the molecular mechanisms underlying preeclampsia-mediated ROP protection
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