VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development

Abstract

Prevention or treatment of lung diseases caused by the failure to form, or destruction of, existing alveoli, as observed in infants with bronchopulmonary dysplasia and adults with emphysema, requires understanding of the molecular mechanisms of alveolar development. In addition to its critical role in gas exchange, the pulmonary circulation also contributes to alveolar morphogenesis and maintenance by the production of paracrine factors, termed "angiocrines," that impact the development of surrounding tissue. To identify lung angiocrines that contribute to alveolar formation, we disrupted pulmonary vascular development by conditional inactivation of the Vegf-A gene during alveologenesis. This resulted in decreased pulmonary capillary and alveolar development and altered lung elastin and retinoic acid (RA) expression. We determined that RA is produced by pulmonary endothelial cells and regulates pulmonary angiogenesis and elastin synthesis by induction of VEGF-A and fibroblast growth factor (FGF)-18, respectively. Inhibition of RA synthesis in newborn mice decreased FGF-18 and elastin expression and impaired alveolarization. Treatment with RA and vitamin A partially reversed the impaired vascular and alveolar development induced by VEGF inhibition. Thus we identified RA as a lung angiocrine that regulates alveolarization through autocrine regulation of endothelial development and paracrine regulation of elastin synthesis via induction of FGF-18 in mesenchymal cells.

Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema

“…It is thus possible that VEGF signalling mediates ATRA-induced HLMVEC angiogenesis. In support of this hypothesis, ATRA-induced foetal sheep PAEC branching was inhibited by a VEGF receptor antagonist,39 and RA-induced lung regeneration in mice was associated with increased VEGFR2 expression 43…”

“…This is supported by prior reports: exogenous ATRA stimulated foetal sheep pulmonary artery endothelial cell (PAEC) proliferation and tube branching in vitro . 39 RA was sufficient to protect pulmonary vascular development and thus maintain alveolarisation in neonatal mice following anti-angiogenic treatment,40 and in a canine model of post-pneumonectomy alveolar regeneration, RA administration preferentially increased microvascular capillary volume and the incidence of double capillaries, thereby enhancing alveolarisation 14…”

Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation

“…Remodeling of the alveolus continues postnatally concomitant with specification and maturation of alveolar type 1 (AT1) and type 2 (AT2) epithelial cells until lung maturity is reached at postnatal day 30 (PN30) in mice and into adolescence in humans (Branchfield et al, 2016; Herring et al, 2014; Mund et al, 2008). Despite the extensive knowledge of earlier stages of lung development including branching morphogenesis, little is known about the cell lineage specific interactions and molecular pathways governing the normal generation of the lung alveolus (Branchfield et al, 2016; El Agha et al, 2014; Yun et al, 2016). Since disruption of this process can be deleterious and result in neonatal diseases such as bronchopulmonary dysplasia (BPD) (Bourbon et al, 2005), a better understanding of the cellular growth and differentiation that occurs during this crucial stage of lung development is required.…”

Retinoic acid signaling in vascular development

“…For example, studies where endothelial cell function is impaired via expression of a dominate negative VEGF receptor or deletion of endothelial adhesion molecule PECAM, lung vascular development is blocked and epithelial branching is severely compromised (DeLisser et al, 2006; Lazarus et al, 2011). Endothelial cells are the main source of RA in the developing lung (Yun, Lorizio, Seedorf, Abman, & Vu, 2016) and RA has an important role in lung development. Studies of Vitamin A deficiency and genetic deletion of RA receptors both show impaired alveolar and lung vascular development (Biesalski & Nohr, 2003; Maden & Hind, 2004; McGowan et al, 2000).…”

“…VEGFA produced by the lung epithelium stimulates endothelial cells to produce RA, and RA acts to drive lung endothelial cell proliferation and tube formation (S. J. Cho, George, Snyder, & Acarregui, 2005; Yun et al, 2016). Evidence suggests RA can regulate lung endothelial cell behavior in both a VEGFA dependent and independent manner (S.…”