Lymphatics thrive on stress: mechanical force in lymphatic development.

The arteries, veins, capillaries and lymphatic vessels that comprise the vertebrate vascular system function to transport blood and lymphatic fluid to and from the tissues. It is therefore unsurprising that development, maintenance and physiology of these structures are strongly influenced by mechanical forces such as pressure and fluid shear stress associated with fluid flow (Hahn and Schwartz, 2008; Culver and Dickinson, 2010). Both embryonic morphogenesis and adult homeostasis of blood vessels appear to be organized so that vessel dimensions are matched to tissue demand. The accompanying paper from Planas-Paz et al (2012) elegantly demonstrates that a similar principle operates for lymphatic development as well. The lymphatic system is composed of a network of blindended, thin-walled capillaries that coalesce into larger vessels, which in turn drain into the venous circulation via the thoracic duct (Schulte-Merker et al, 2011). The primary role of lymphatics is to remove the protein-rich interstitial fluid from the extracellular spaces, thereby reducing interstitial pressure and maintaining the overall fluid balance in the body. The development and maintenance of the lymphatic vasculature is orchestrated by several key players including homeobox transcription factors of the SOX F family, lymphatic-specific transcription factor Prox1, VEGF-C and its receptor VEGFR3. Lymphatic development in mice proceeds in two distinct steps (Schulte-Merker et al, 2011). The first is an induction of polarized expression of Sox18 transcription factor in cardinal vein endothelial cells at around E9.5. This cell population then acquires expression of Prox1, a prospero-related homeodomain transcription factor that, together with COUP-TFII, converts them to lymphatic fate. The newly specified lymphatic endothelial cells then sprout out of the cardinal vein to form jugular lymphatic sacs. The second step that takes place around E13.5 is the sprouting of lymphatic sacs leading to formation of the lymphatic vasculature. Little is known about signals responsible for initiation of these events, except that lymphatic sprouting clearly requires VEGF-C/VEGFR3 signalling. The study by Planas-Paz et al (2012) shows that an increase in tissue hydrostatic pressure promotes lymphangiogenesis. The data suggest that increasing tissue turgor is due to increasing filtration of plasma from the arterial circulation into the interstitial space as the vascular system grows and expands. This pressure is suggested to stretch the nascent lymphatics, triggering proliferation of lymphatic endothelial cells and hence enlargement of lymphatic vessels (Figure 1). The authors propose that pressure-induced activation of VEGFR3 mediated by b1 integrin, perhaps with the involvement of Src, is the key step. VEGF-C also is required for this