Jazzing up vessel growth

In this issue of Blood, Niessen and colleagues identify a critical role for signaling through the TGFβ pathway in postnatal lymphatic vessel growth. In vitro studies demonstrate that TGFβ and BMP receptors are expressed and function in lymphatic endothelial cells. Injection of soluble receptor proteins that block signaling by this family of ligands interrupts the terminal stages of microvascular lymphatic remodeling in neonatal mice. These findings identify a signaling pathway that regulates both blood and lymphatic vessel growth and underscore the need for more sophisticated genetic and pharmacologic approaches to better define how core signaling pathways orchestrate growth of the 2 mammalian vasculatures.

Mammals have 2 vascular networks that operate in parallel but develop in series. Blood vessels deliver oxygen and nutrients, whereas lymphatic vessels drain excess interstitial fluid, transport absorbed fats from the intestine, and coordinate immune cell movements and responses.¹  The heart and blood vascular network forms early during mammalian development. In contrast, lymphatic vessels arise later from venous endothelial cell precursors that exit the vein and sprout to form a new vascular network.^2,3  Defining the signaling pathways that guide blood and lymphatic vessel growth is a priority because such pathways have been linked to both congenital and acquired human vascular diseases.

Genetic loss-of-function studies in mice have defined core signaling pathways that regulate blood vessel development, including the vascular endothelial growth factor (VEGF), angiopoietin, and transforming growth factor (TGF)β pathways. In contrast, a molecular understanding of lymphatic vessel development has been restricted to a handful of pathways that disturb lymphatic but not blood vessel growth and therefore permit embryonic survival to a late enough time point to observe lymphatic phenotypes. However, gene-expression studies reveal that many of the core signaling pathways critical for blood vessel growth are also expressed in lymphatic endothelial cells. Defining the lymphatic role of these necessary pathways will require sophisticated genetic and pharmacologic approaches that target lymphatic vessels but spare blood vessels.

Loss of TGFβ signaling underlies the human vascular disease hereditary hemorrhagic telangiectasia (HHT), and deletion of the TGFβ receptor ALK1 in mice results in the formation of embryonic arteriovenous malformations like those observed in HHT and death in midgestation.⁴  Niessen et al noted that lymphatic endothelial cells expressed functional TGFβ family receptors similar to those in blood endothelial cells, suggesting that this pathway participates in lymphatic as well as blood vessel growth.⁵  To test this hypothesis, neonatal mice were injected with receptor ectodomain-Fc fusion proteins, a decoy receptor strategy that takes advantage of the fact that lymphatic growth begins late and extends into the postnatal period. Injection of ALK1-Fc fusion proteins resulted in chylous ascites due to a failure of terminal lymphatic microvessels to mature, while injection of soluble receptors for related bone morphogenetic protein ligands conferred similar but less dramatic lymphatic vascular defects. The defects conferred by soluble receptor proteins were maximal when administered shortly after birth, suggesting that they interfere with the growth and maturation of developing vessels rather than the integrity of mature vessels. Unexpectedly, a synergistic effect was observed with inhibition of both TGFβ and VEGF-C signaling, suggesting that the roles of these signaling pathways in lymphangiogenesis overlap.

These findings establish an unsuspected role for TGFβ-type signaling in lymphatic vessel growth and provide a glimpse of what might be learned about the role of other core signaling pathways in different vascular beds using new in vivo approaches. The blood vessel phenotypes associated with loss of TGFβ-ALK1 signaling are believed to arise due to defects in endothelial arteriovenous identity. In contrast, the lymphatic vessel defects observed by Niessen et al appear more connected to endothelial proliferation than to endothelial identity. That the pathway serves such different roles in these 2 vascular contexts is unanticipated and hints at greater complexity and versatility than have been previously suspected. The development of new genetic approaches that enable more precise spatial and temporal gene deletion in the endothelium and of creative pharmacologic approaches such as that used by Niessen et al is expected to provide a more complete understanding of the diverse roles served by core vascular signaling pathways in blood and lymphatic vessels.