uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Pulmonary Lymphangiectasia Resulting From Vascular Endothelial Growth Factor-C Overexpression During a Critical Period
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
Show others and affiliations
2014 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 114, no 5, 806-822 p.Article in journal (Refereed) Published
Abstract [en]

Rationale: Lymphatic vessels in the respiratory tract normally mature into a functional network during the neonatal period, but under some pathological conditions they can grow as enlarged, dilated sacs that result in the potentially lethal condition of pulmonary lymphangiectasia. Objective: We sought to determine whether overexpression of the lymphangiogenic growth factor (vascular endothelial growth factor-C [VEGF-C]) can promote lymphatic growth and maturation in the respiratory tract. Unexpectedly, perinatal overexpression of VEGF-C in the respiratory epithelium led to a condition resembling human pulmonary lymphangiectasia, a life-threatening disorder of the newborn characterized by respiratory distress and the presence of widely dilated lymphatics. Methods and Results: Administration of doxycycline to Clara cell secretory protein-reverse tetracycline-controlled transactivator/tetracycline operator-VEGF-C double-transgenic mice during a critical period from embryonic day 15.5 to postnatal day 14 was accompanied by respiratory distress, chylothorax, pulmonary lymphangiectasia, and high mortality. Enlarged sac-like lymphatics were abundant near major airways, pulmonary vessels, and visceral pleura. Side-by-side comparison revealed morphological features similar to pulmonary lymphangiectasia in humans. The condition was milder in mice given doxycycline after age postnatal day 14 and did not develop after postnatal day 35. Mechanistic studies revealed that VEGF recptor (VEGFR)-3 alone drove lymphatic growth in adult mice, but both VEGFR-2 and VEGFR-3 were required for the development of lymphangiectasia in neonates. VEGFR-2/VEGFR-3 heterodimers were more abundant in the dilated lymphatics, consistent with the involvement of both receptors. Despite the dependence of lymphangiectasia on VEGFR-2 and VEGFR-3, the condition was not reversed by blocking both receptors together or by withdrawing VEGF-C. Conclusions: The findings indicate that VEGF-C overexpression can induce pulmonary lymphangiectasia during a critical period in perinatal development.

Place, publisher, year, edition, pages
2014. Vol. 114, no 5, 806-822 p.
Keyword [en]
chylothorax, lung, lymphatic vessels, lymphangiogenesis, lymphangiomatosis, pulmonary, pulmonary edema, VEGFR-2, VEGFR-3
National Category
Cardiac and Cardiovascular Systems Hematology
URN: urn:nbn:se:uu:diva-227943DOI: 10.1161/CIRCRESAHA.114.303119ISI: 000335586900013OAI: oai:DiVA.org:uu-227943DiVA: diva2:733004
Available from: 2014-07-07 Created: 2014-07-02 Last updated: 2014-07-07Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Testini, ChiaraClaesson-Welsh, Lena
By organisation
Cancer and Vascular Biology
In the same journal
Circulation Research
Cardiac and Cardiovascular SystemsHematology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 278 hits
ReferencesLink to record
Permanent link

Direct link