Developmental Biology in the Vasculature—Review Series
Series Editor: Mark Majesky PhD
In this issue of the ATVB, we present a series of concise review articles on the development of blood and lymphatic vessels. These articles discuss the fundamental mechanisms at work to form and remodel the vascular system. They also address current issues and controversies in the field and propose new directions for future investigation.
The process of vascular development begins with formation of angioblasts and their assembly into a primitive vascular plexus. In a review of this process titled “The Opening Act: Vasculogenesis and the Origins of Circulation,” Suk-Won Jin and Cam Patterson1 discuss the interplay between predetermined genetic mechanisms for vasculogenesis and important epigenetic factors that modify these genetic pathways and shape the outcome of the process. In particular, the important roles played by hemodynamic forces and hypoxia-mediated responses for angioblast formation, differentiation and vascular plexus formation are examined. Once formed, nascent blood vessels require interactions between endothelial cells and mural cell partners to exchange essential survival factors and promote maturation responses in both cell types. This reciprocal signaling is responsive to blood flow–dependent shear forces acting on endothelial cells and requires the integration of multiple paracrine signaling pathways. In the article “Endothelial Mural Cell Signaling in Vascular Development and Angiogenesis,” Christer Betsholtz and colleagues2 discuss the individual factors that have been identified as important players in endothelial cell–mural cell interactions and address the question of how these factors interact to stabilize newly formed blood vessels and promote their differentiation and maturation.
The primitive vascular system formed in early embryos undergoes continuous growth and remodeling to support development of the embryo itself, and to adapt to the increases in mass of individual target organs and tissues that accompany embryonic growth. This remodeling process involves both formation of new vessels and regression of preexisting vessels. Vascular network remodeling continues after birth and is essential throughout life to ensure that vascular supply meets constantly changing demands for tissue perfusion. In the article “Mechanisms of Vessel Branching: Filopodia on Endothelial Tip Cells Lead the Way,” Peter Carmeliet and coworkers3 focus on key early steps in angiogenesis and discuss mechanisms by which endothelial sprouts are formed by the coordinate activities of tip, stalk, and phalanx cells. The critical roles of endothelial tip cell filopodia in exploring the local environment and providing feedback signals that guide sprout formation are discussed in detail. A fully functional vascular system requires a network of lymphatic vessels to maintain fluid homeostasis. The lymphatic system is essential for embryonic development and leukocyte trafficking and is a vehicle for tumor metastasis. However, basic molecular mechanisms that underlie lymphangiogenesis are incompletely understood. Likewise, effective therapeutic approaches to promote or inhibit this process are largely lacking. In the article “G Protein–Coupled Receptors as Potential Drug Targets for Lymphangiogenesis and Lymphatic Vascular Disease” by William Dunworth and Kathleen Caron,4 the role of G protein–coupled receptors (GPCRs) as both essential mediators of lymphatic vessel formation in the embryo and as attractive therapeutic targets for lymphatic disorders in adults is reviewed. A focus on the role of adrenomedulin receptors in lymphangiogenesis serves as a starting point for a forward-looking analysis of the therapeutic potentials of this class of GPCRs as drug targets for diseases of the lymphatic system.
In summary, this series of review articles by established leaders in the field will serve as both a valuable resource in rapidly moving areas of vascular biology and as guideposts for future work on central questions related to vascular development and remodeling that are highlighted by the authors.
Sources of Funding
Supported by National Institutes of Health grant HL-19242 and by the Carolina Cardiovascular Biology Center.
Jin S-W, Patterson C. The opening act: vasculogenesis and the origins of circulation. Arterioscler Thromb Vasc Biol. 2009; 29: 623–629.
Gaengel K, Genové G, Armulik A, Betsholtz C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol. 2009; 29: 630–638.
De Smet F, Segura I, De Bock K, Hohensinner PJ, Carmeliet P. Mechanisms of vessel branching: filopodia on endothelial tip cells lead the way. Arterioscler Thromb Vasc Biol. 2009; 29: 639–649.
Dunworth WP, Caron KM. G protein–coupled receptors as potential drug targets for lymphangiogenesis and lymphatic vascular diseases. Arterioscler Thromb Vasc Biol. 2009; 29: 650–656.