Endothelium-Microenvironment Interactions in the Developing Embryo and in the Adult  Kristy Red-Horse, Yongping Crawford, Farbod Shojaei, Napoleone Ferrara  Developmental Cell  Volume 12, Issue 2, Pages 181-194 (February 2007) DOI: 10.1016/j.devcel.2007.01.013 Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 1 Architectural Features of the Vasculature The circulation is structured such that oxygen-rich blood leaving the heart is delivered to different tissues through arterial vessels that are invested with a significant layer of vascular smooth muscle. Within the tissue, these vessels branch into smaller capillaries capable of mediating oxygen and nutrient exchange. Capillaries are primarily associated with pericytes and can develop tissue-specific characteristics. For example, constitutive VEGF expression in certain endocrine glands promotes a fenestrated (gapped) endothelial layer, while astrocyte-derived TGFβ and Ang-1 induces tight junctions characteristic of the blood-brain barrier. Following exchange, capillaries converge, forming venous vessels that deliver deoxygenated blood back to the heart. In general, veins are lower resistance and have larger lumens than arteries, with a reduced amount of vascular smooth muscle coverage. Developmental Cell 2007 12, 181-194DOI: (10.1016/j.devcel.2007.01.013) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 2 Blood Vessel Maturation Requires Numerous Interactions between Endothelial Cells and the Surrounding Environment Stable vessels are invested by mural cells (pericytes and/or vascular smooth muscle) that, along with endothelial cells, secrete extracellular matrix (ECM) components that form the vascular basement membrane (BM). Endothelial cell-derived signals, including PDGF-B, are critical for attracting mural cells to the vessel wall and triggering their differentiation. In reciprocal interactions, mural cells can both positively (green) and negatively (red) affect endothelial growth and development. These and other accessory cell types, such as fibroblasts and hematopoietic cells, actively participate in angiogenesis. They produce angiogenic ECM components and growth factors (VEGF) as well as stimulate ECM remodeling through MMP secretion. ECM cleavage can also yield angiostatic fragments, underscoring the complex balance between pro- and antiangiogenic factors during vascular remodeling. Developmental Cell 2007 12, 181-194DOI: (10.1016/j.devcel.2007.01.013) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 3 Model for Arterio-Venous Specification in the Axial Vessels of the Developing Embryo Sonic hedgehog secreted by the notochord and floorplate induces VEGF production by adjacent somites. VEGF arterializes the dorsal aorta, inducing Notch-1 and Delta-like-4 expression through a mechanism involving the transcription factors Foxc1 and Foxc2. Notch signaling and downstream effectors promote expression of the arterial marker ephrinB2 and inhibit the venous marker EphB4. In the cardinal vein, COUP-TFII is required for strong EphB4 expression and venous differentiation through inhibition of the Neuropilin and effectively the downstream Notch pathway. Developmental Cell 2007 12, 181-194DOI: (10.1016/j.devcel.2007.01.013) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 4 Endothelial-Derived Signals Influence Organ Development and Function Several examples exist describing the direct impact of endothelial cells on different processes in embryonic and adult tissue. Developmental Cell 2007 12, 181-194DOI: (10.1016/j.devcel.2007.01.013) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 5 Contribution of Different Stromal Cell Types during Tumor Angiogenesis Solid lesions consist of tumor cells enmeshed with various stromal types, which can include fibroblasts and hematopoietic and endothelial cells. These components communicate with each other and distant tissues (i.e., bone marrow) to affect the state of the vasculature and, as a consequence, tumor growth. Examples of angiogenic interactions are depicted in the figure. Cancer-associated fibroblasts produce CXCL12, which recruits bone marrow-derived endothelial progenitor cells. Fibroblasts and hematopoietic as well as tumor cells are an abundant source of angiogenic molecules such as VEGF family members (e.g., VEGF-A, VEGF-B, PlGF), FGF, and MMPs. As discussed in the text, there is significant debate in the field regarding the contribution of bone marrow-derived cells to the endothelial cell layer. Developmental Cell 2007 12, 181-194DOI: (10.1016/j.devcel.2007.01.013) Copyright © 2007 Elsevier Inc. Terms and Conditions