Regulation of tissue morphogenesis by endothelial cell-derived signals

Abstract

Endothelial cells (ECs) form an extensive network of blood vessels that has numerous essential functions in the vertebrate body. In addition to their well-established role as a versatile transport network, blood vessels can induce organ formation or direct growth and differentiation processes by providing signals in a paracrine (angiocrine) fashion. Tissue repair also requires the local restoration of vasculature. ECs are emerging as important signaling centers that coordinate regeneration and help to prevent deregulated, disease-promoting processes. Vascular cells are also part of stem cell niches and have key roles in hematopoiesis, bone formation, and neurogenesis. Here, we review these newly identified roles of ECs in the regulation of organ morphogenesis, maintenance, and regeneration.

Keywords: angiocrine signaling; angiogenesis; bone marrow; endothelial cells; liver; lung; organ morphogenesis; vascular niche.

Figure 1. Role of endothelial cells during organogenesis

(a) Endothelial cells contribute to the coronary vasculature and endocardium during early heart development. Endocardial cells release Nrg1, which signals to myocardial cells expressing the receptors ErbB2 and ErbB4. Myocardial cells release VEGF acting on ECs. Notch ligands expressed in myocardium and endocardium signal through endocardial Notch receptors. Bmp2 released from the myocardium acts on the endocardium during heart valve formation. (b) ECs play crucial role in the development of kidney glomeruli. Podocytes recruit ECs by expressing VEGF and, conversely, ECs secrete MMP2 and PDGF-B. Sema 3a and Sema 3c released by podocytes regulate kidney vascular morphogenesis. Both ECs and Podocytes synthesize glomerular basement membrane components such as Laminin-α5β2γ1 (LM521). (c) During liver bud formation, hepatic endoderm migrates into the septum transversum mesenchyme along with ECs. Endoderm cells stimulate angiogenesis by releasing VEGF. ECs control Wnt and Notch signaling in the developing hepatic endoderm. (d) ECs in close proximity to endoderm promote pancreatic bud formation. Sphingosine-1-phosphate (S1P) derived from vascular cells or the circulation promotes budding of pancreatic endoderm (green cells). S1P-receptors (S1PR) are expressed by endothelial cells (orange) and mesenchymal cells (grey). (e) Dorsal aorta-derived BMPs induce mesenchymal SDF1 and neuregulin-1 expression, which attracts SA progenitors. BMP signaling also controls the segregation of progenitors forming the adrenal medulla and sympathetic ganglions, which involves neuregulin-ErbB signaling.

Figure 2. Endothelial cells in lung regeneration

Compensatory lung growth following unilateral pneumonectomy occurs through VEGF and FGF signaling involving the receptors VEGFR2 and FGFR1 on pulmonary ECs. These signaling cascades induce expression of MMP14, which then generates EGF-like ligands by processing of heparin binding EGF-like growth factor (HB-EGF) and the laminin5 γ2 subunit. This leads to the activation of EGF receptor (EGFR) on alveolar epithelial cells and bronchioalveolar stem cells (BASCs), which drives expansion of BASCs and generation of epithelial cells. ECs also regulate BASC differentiation choices during regeneration. Post-injury release of BMP4 triggers NFAT-dependent TSP1 expression in ECs, which promotes alveolar differentiation and repair. Bottom: Release of pro-angiogenic signals after injury or infection in lung promotes endothelial cell expansion, which in turn causes enhanced release of angiocrine factors to promote regeneration.

Figure 3. Liver endothelium in regeneration and fibrosis

Liver sinusoidal ECs play critical roles after liver injury in mediating regeneration and fibrosis. LSECs release hepatocyte growth factor and, in turn, hepatocytes release VEGF (top). During the inductive phase, hepatocyte proliferation is enabled by decreased endothelial expression of Ang2 leading to reduced TGFβ1 secretion. Vegfr2-Id1 mediated release of Wnt2 and HGF by LSECs also promotes growth of hepatocytes. Recovery in Ang2 levels upregulates VEGFR2 and thereby promotes vessel growth in the angiogenic phase. LSEC release SDF1 (Cxcl12) to attract hepatic stellate cells, which also release SDF1 to attract immune cells. Hepatic Stellate Cells also express high levels of HGF after partial hepatectomy to overcome the inhibitoy effect of TGFβ1. While CXCR7 in LSECs promotes angiocrine signaling and regeneration, CXCR4 generates a pro-fibrotic niche. Bottom: Liver regeneration involves inductive and angiogenic phases that are tightly controlled by LSECs. Angiocrine factors make the decision between fibrosis and regeneration after injury.

Figure 4. Functional roles of the bone vasculature

Angiogenesis in bone is promoted by VEGF secretion from chondrocytes and osteoblasts. Two novel vessel subtypes, termed type H and type L, have been identified in the skeletal system. Type H vessels require Notch and HIF signaling for their maintenance and secrete osteogenic factors and Noggin acting on osteoprogenitor cells and chondrocytes, which are important sources of VEGF leading to coupling of angiogenesis and osteogenesis. Angiocrine factors (such as SDF1/Cxcl12 and SCF) released by endothelium and pericytes have been also shown to support HSCs, which express the cognate receptors CXCR4 and c-Kit, respectively. Although ECs, perivascular, neural, and mesenchymal cells are involved in HSC maintenance, the exact composition and localization of stem cell niches as well as the roles of vessel subtypes require further investigation.

Figure 5. Vascular niche for neurogenesis

Neural stem/progenitor cells in the adult reside in a specialized vascular niche and constitutively express VEGF to promote vasoprotection and angiogenesis. Endothelial expression of growth factors such as BDNF, VEGF and PEDF has neuroprotective function and promotes NSC self-renewal. ECs also regulate stem cell quiescence and promote stemness through membrane-anchored (ephrin-B2, Jagged1) or secreted (SDF1) signals.