Investigation of the mechanisms of VEGF-mediated compensatory lung growth: the role of the VEGF heparin-binding domain.

Animals Cell Proliferation Drug Design Endothelial Cells / metabolism Exercise Test Hematocrit Heparin / chemistry Humans Lung / metabolism Male Mice Mice, Inbred C57BL Microcirculation Pneumonectomy Protein Domains Signal Transduction Vascular Endothelial Growth Factor A / chemistry

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
04 06 2021
Historique:
received: 14 11 2020
accepted: 17 05 2021
entrez: 5 6 2021
pubmed: 6 6 2021
medline: 16 11 2021
Statut: epublish

Résumé

Morbidity and mortality for neonates with congenital diaphragmatic hernia-associated pulmonary hypoplasia remains high. These patients may be deficient in vascular endothelial growth factor (VEGF). Our lab previously established that exogenous VEGF164 accelerates compensatory lung growth (CLG) after left pneumonectomy in a murine model. We aimed to further investigate VEGF-mediated CLG by examining the role of the heparin-binding domain (HBD). Eight-week-old, male, C57BL/6J mice underwent left pneumonectomy, followed by post-operative and daily intraperitoneal injections of equimolar VEGF164 or VEGF120, which lacks the HBD. Isovolumetric saline was used as a control. VEGF164 significantly increased lung volume, total lung capacity, and alveolarization, while VEGF120 did not. Treadmill exercise tolerance testing (TETT) demonstrated improved functional outcomes post-pneumonectomy with VEGF164 treatment. In lung protein analysis, VEGF treatment modulated downstream angiogenic signaling. Activation of epithelial growth factor receptor and pulmonary cell proliferation was also upregulated. Human microvascular lung endothelial cells (HMVEC-L) treated with VEGF demonstrated decreased potency of VEGFR2 activation with VEGF121 treatment compared to VEGF165 treatment. Taken together, these data indicate that the VEGF HBD contributes to angiogenic and proliferative signaling, is required for accelerated compensatory lung growth, and improves functional outcomes in a murine CLG model.

Identifiants

DOI: 10.1038/s41598-021-91127-0 PMID: 34088930 PMC: PMC8178332
pubmed: 34088930
doi: 10.1038/s41598-021-91127-0
pii: 10.1038/s41598-021-91127-0
pmc: PMC8178332
doi:

Substances chimiques

VEGFA protein, human 0
Vascular Endothelial Growth Factor A 0
vascular endothelial growth factor A, mouse 0
Heparin 9005-49-6

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

11827

Subventions

Organisme : NHLBI NIH HHS
ID : T32 HL007734
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : NIH HHS
ID : 5T32HL007734
Pays : United States

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Auteurs

Lumeng J Yu (LJ)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA.

Victoria H Ko (VH)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA.

Duy T Dao (DT)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA.

Jordan D Secor (JD)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA.

Amy Pan (A)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA.

Bennet S Cho (BS)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA.

Paul D Mitchell (PD)

Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, 02115, USA.

Hiroko Kishikawa (H)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA.

Diane R Bielenberg (DR)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

Mark Puder (M)

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. mark.puder@childrens.harvard.edu.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA. mark.puder@childrens.harvard.edu.

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