Vascular endothelial growth factor accelerates compensatory lung growth by increasing the alveolar units

Dao, Duy T.; Nandivada, Prathima; Vuong, Jacqueline T; Anez‐Bustillos, Lorenzo; Pan, Amy; Kishikawa, Hiroko; Mitchell, Paul D.; Baker, Meredith A.; Fell, Gillian L.; Martin, Thomas R.; Puder, Mark

doi:10.1038/pr.2018.41

Cited by 19 publications

(22 citation statements)

References 24 publications

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“…This result was confirmed with an EGF ELISA ( P = 0.04) (Fig 2G). An increase in EGF expression has also been demonstrated with exogenous VEGF administration after left PNX [11]. Given that VEGFR1 increased endogenous production of VEGF, this concurrent upregulation of EGF is consistent with our previously published work.…”

Section: Resultssupporting

confidence: 91%

“…Activation of HIF2α-VEGF in turn elicited a series of responses that were essential to lung growth and maturation. The upregulation of EGF is notable as it is an important epithelial cell mitogen, whose levels have been shown to increase with exogenous VEGF administration [11]. This probably played a role in promoting lung maturation, as evidenced by increased production of surfactant proteins B and C. Given that AECII is also responsible for surfactant synthesis, it is therefore not surprising that both hypoxia and VEGF have been shown to be important promoters of SP-C production [27,28].…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of the VEGF pathway is implicated in the pathogenesis of many pulmonary diseases of the neonate, most notably congenital diaphragmatic hernia (CDH) [6,7] and bronchopulmonary dysplasia (BPD) [8,9]. In addition, signaling from VEGFR2 is critical for physiologic processes such as compensatory lung growth (CLG) [10], and provision of VEGF accelerates alveolar regeneration after unilateral pneumonectomy (PNX) [11]. Targeting the VEGF pathway, therefore, can provide a new strategy for improving lung growth and respiratory insufficiency encountered in diseases such as CDH and BPD.…”

Section: Introductionmentioning

confidence: 99%

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A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor

et al. 2018

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Exogenous vascular endothelial growth factor (VEGF) accelerates compensatory lung growth (CLG) in mice after unilateral pneumonectomy. In this study, we unexpectedly discovered a method to enhance CLG with a VEGF inhibitor, soluble VEGFR1. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily intraperitoneal (ip) injection of either saline (control) or 20 μg/kg of VEGFR1-Fc. On post-operative day (POD) 4, mice underwent pulmonary function tests (PFT) and lungs were harvested for volume measurement and analyses of the VEGF signaling pathway. To investigate the role of hypoxia in mediating the effects of VEGFR1, experiments were repeated with concurrent administration of PT-2385, an inhibitor of hypoxia-induced factor (HIF)2α, via orogastric gavage at 10 mg/kg every 12 hours for 4 days. We found that VEGFR1-treated mice had increased total lung capacity (P = 0.006), pulmonary compliance (P = 0.03), and post-euthanasia lung volume (P = 0.049) compared to control mice. VEGFR1 treatment increased pulmonary levels of VEGF (P = 0.008) and VEGFR2 (P = 0.01). It also stimulated endothelial proliferation (P < 0.0001) and enhanced pulmonary surfactant production (P = 0.03). The addition of PT-2385 abolished the increase in lung volume and endothelial proliferation in response to VEGFR1. By paradoxically stimulating angiogenesis and enhancing lung growth, VEGFR1 could represent a new treatment strategy for neonatal lung diseases characterized by dysfunction of the HIF-VEGF pathway.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor

et al. 2018

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“…Furthermore, the increase in lung volume was supported by an improvement in total lung capacity and pulmonary compliance on pulmonary mechanical studies. Since pulmonary compliance is a measure of volume change against applied pressure and total lung capacity is a direct measure of lung volume in live animals, these parameters have been shown to correlate with lung growth and improve during the process of CLG [ 38 ]. Despite the lack of statistical significance, there was also an improvement in walking distance, rest time, and basic and fine movements in VEGF-treated mice on POD 10, especially in the post-treadmill measurements.…”

Section: Discussionmentioning

confidence: 99%

Intranasal delivery of VEGF enhances compensatory lung growth in mice

et al. 2018

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Vascular endothelial growth factor (VEGF) has previously been demonstrated to accelerate compensatory lung growth (CLG) in mice and may be a useful therapy for pulmonary hypoplasia. Systemic administration of VEGF can result in side effects such as hypotension and edema. The aim of this study was to explore nasal delivery as a route for intrapulmonary VEGF administration. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily nasal instillation of VEGF at 0.5 mg/kg or isovolumetric saline. Lung volume measurement, morphometric analysis, and protein expression studies were performed on lung tissues harvested on postoperative day (POD) 4. To understand the mechanism by which VEGF accelerates lung growth, proliferation of human bronchial epithelial cells (HBEC) was assessed in a co-culture model with lung microvascular endothelial cells (HMVEC-L) treated with and without VEGF (10 ng/mL). The assay was then repeated with a heparin-binding EGF-like growth factor (HB-EGF) neutralizing antibody ranging from 0.5–50 μg/mL. Compared to control mice, the VEGF-treated group displayed significantly higher lung volume (P = 0.001) and alveolar count (P = 0.005) on POD 4. VEGF treatment resulted in increased pulmonary expression of HB-EGF (P = 0.02). VEGF-treated HMVEC-L increased HBEC proliferation (P = 0.002) while the addition of an HB-EGF neutralizing antibody at 5 and 50 μg/mL abolished this effect (P = 0.01 and 0.002, respectively). These findings demonstrate that nasal delivery of VEGF enhanced CLG. These effects could be mediated by a paracrine mechanism through upregulation of HB-EGF, an epithelial cell mitogen.

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“…Directly in this line, postnatal alveologenesis was documented to be dependent on FoxF1 signaling in Kit ϩ (also called c-Kit) endothelial progenitor cells (488). These reports are interesting, given a study reporting that Foxf1 decreases endothelial VEGF signaling, since a third study effectively connects these two ideas, where exogenous VEGF administration accelerated compensatory lung growth after unilateral pneumonectomy (108). Thus, it appears that Foxf1 regulates VEGF signaling in the lung epithelium, which in turn, regulates compensatory lung growth after pneumonectomy.…”

Section: Other Molecular Mediators Of Alveolarization and Bpdmentioning

confidence: 93%

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

Lignelli

Palumbo

Myti

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

111

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Bronchopulmonary dysplasia (BPD) is the most common cause of morbidity and mortality in preterm infants. A key histopathological feature of BPD is stunted late lung development, where the process of alveolarization—the generation of alveolar gas exchange units—is impeded, through mechanisms that remain largely unclear. As such, there is interest in the clarification both of the pathomechanisms at play in affected lungs, and the mechanisms of de novo alveoli generation in healthy, developing lungs. A better understanding of normal and pathological alveolarization might reveal opportunities for improved medical management of affected infants. Furthermore, disturbances to the alveolar architecture are a key histopathological feature of several adult chronic lung diseases, including emphysema and fibrosis, and it is envisaged that knowledge about the mechanisms of alveologenesis might facilitate regeneration of healthy lung parenchyma in affected patients. To this end, recent efforts have interrogated clinical data, developed new—and refined existing—in vivo and in vitro models of BPD, have applied new microscopic and radiographic approaches, and have developed advanced cell-culture approaches, including organoid generation. Advances have also been made in the development of other methodologies, including single-cell analysis, metabolomics, lipidomics, and proteomics, as well as the generation and use of complex mouse genetics tools. The objective of this review is to present advances made in our understanding of the mechanisms of lung alveolarization and BPD over the period 1 January 2017–30 June 2019, a period that spans the 50th anniversary of the original clinical description of BPD in preterm infants.

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Vascular endothelial growth factor accelerates compensatory lung growth by increasing the alveolar units

Cited by 19 publications

References 24 publications

A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor

A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor

Intranasal delivery of VEGF enhances compensatory lung growth in mice

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

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