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However, maternal and fetal genetic factors and the molecular mechanisms remain unclear. We investigated the relationship between LBW and lung function with Mendelian randomisation analyses and studied angiogenesis in a low protein diet rat model of IUGR. Our data indicate a possible association between LBW and reduced FEV1 (p\u2009=\u20095.69E\u221218, MR-PRESSO) and FVC <jats:bold>(<\/jats:bold>6.02E-22, MR-PRESSO). Complimentary, we demonstrated two-phased perinatal programming after IUGR. The intrauterine phase (embryonic day 21) is earmarked by a reduction of endothelial cell markers (e.g. CD31) as well as mRNA expression of angiogenic factors (e.g., Vegfa, Flt1, Klf4). Protein analysis identified an activation of anti-angiogenic mTOR effectors. In the postnatal phase, lung capillaries (&lt;\u200920\u00a0\u00b5m) were significantly reduced, expression of CD31 and VE-Cadherin were unaffected, whereas SMAD1\/5\/8 signaling and Klf4 protein were increased (p\u2009&lt;\u20090.01). Moreover, elevated proteolytic activity of MMP2 and MMP9 was linked to a 50% reduction of lung elastic fibres. In conclusion, we show a possible link of LBW in humans and reduced lung function in adulthood. Experimental IUGR identifies an <jats:italic>intrauterine phase<\/jats:italic> with inhibition of angiogenic signaling, and a <jats:italic>postnatal phase<\/jats:italic> with proteolytic activity and reduced elastic fibres.<\/jats:p>","DOI":"10.1038\/s41598-020-79245-7","type":"journal-article","created":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T11:02:37Z","timestamp":1609153357000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mendelian randomization and experimental IUGR reveal the adverse effect of low birth weight on lung structure and function"],"prefix":"10.1038","volume":"10","author":[{"given":"Celien","family":"Kuiper-Makris","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Zanetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Vohlen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luise","family":"Fahle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarete","family":"Odenthal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Felderhoff-M\u00fcser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"D\u00f6tsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Alejandre Alcazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,28]]},"reference":[{"key":"79245_CR1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.jpeds.2017.12.059","volume":"196","author":"IM Beune","year":"2018","unstructured":"Beune, I. 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