Peter BalukAngiogenesis and Lymphangiogenesis in Mouse Airways
Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA
Changes in the blood and lymphatic vasculature contribute to many biological processes suchdevelopment and pathological conditions including inflammation and cancer. Therefore, it is useful
to have in vivo experimental preclinical models where blood vessels and lymphatics can be easily
examined and subtle changes in them can be observed. The mouse trachea presents an ideal
stage where these vascular actors can play very different roles depending on their developmental
age, environment, and stimuli acting on them.
Tracheas of pathogen-free adult mice have a stereotyped two-dimensional network of bloodvessels and lymphatics. Individual arterioles, capillary, venules and accompanying pericytes andsmooth muscle cells can all be recognized (1). In newborn mice, the vascular network is much
more primitive in appearance (2). It is rapidly remodeled over the first few postnatal days into thehierarchical adult network. The changes involve vascular regression followed by angiogenesis andare driven by changes in hypoxia and mechanical forces. Transgenic over-expression of VEGF-A inepithelial cells of the adult mouse trachea induces the rapid growth of blood vessels by angiogenicsprouting, but no lymphangiogenesis (3). The newly formed blood vessels also rapidly regress
when the stimulus is turned off. In contrast, chronic inflammation as a result of airway bacterial
infection with Mycoplasma pulmonis induces more complex responses from blood vessels andlymphatics, probably resulting from the concurrent influx of leukocytes and induction of multiple
inflammatory genes (4, 5). An early change is vascular remodeling by lateral enlargement, whereby
small capillaries gradually transform into venules capable of supporting leukocyte adhesion andplasma extravasation (4, 5). At later stages, small blood vessels grow by angiogenic sprouting.
Lymphatics also grow by sprouting, driven by VEGFR-3 signaling (5). A surprising feature of the
newly formed lymphatics is their persistence when the stimulus that originally induced them has
been removed (5, 6). We conclude that the blood vessels and lymphatics of mouse trachea display
an extraordinary plasticity of response and are an excellent system for studying vascular biology.
1) McDonald DM, Yao LC, Baluk P (2011). Dynamics of airway blood vessels and lymphatics:
lessons from development and inflammation. Proc Am Thorac Soc. 8:504-7. PubMed: 22052927.
2) Ni A, Lashnits E, Yao LC, Baluk P, McDonald DM (2010). Rapid remodeling of airway vasculararchitecture at birth. Dev Dyn. 239:2354-66. PubMed: 20730909.
3) Baluk P, Lee CG, Link H, Ator E, Haskell A, Elias JA, McDonald DM (2004). Regulated
angiogenesis and vascular regression in mice overexpressing vascular endothelial growth factor inairways. Am J Pathol. 165:1071-85. PubMed: 15466375.
4) Baluk P, Yao LC, Feng J, Romano T, Jung SS, Schreiter JL, Yan L, Shealy DJ, McDonald DM(2009). TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway
inflammation in mice. J Clin Invest. 119:2954-64. PubMed: 19759514.
5) Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ, Jeltsch M, Petrova TV,Pytowski B, Stacker SA, Ylä-Herttuala S, Jackson DG, Alitalo K, McDonald DM (2005).
Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J ClinInvest. 115:247-57. PubMed: 15668734.

6) Yao LC, Baluk P, Feng J, McDonald DM (2010). Steroid-resistant lymphatic remodeling inchronically inflamed mouse airways. Am J Pathol. 176:1525-41. PubMed: 20093490.