The Functional Implications of Endothelial Gap Junctions and Cellular Mechanics in Vascular Angiogenesis

Abstract

Angiogenesis-the sprouting and growth of new blood vessels from the existing vasculature-is an important contributor to tumor development, since it facilitates the supply of oxygen and nutrients to cancer cells. Endothelial cells are critically affected during the angiogenic process as their proliferation, motility, and morphology are modulated by pro-angiogenic and environmental factors associated with tumor tissues and cancer cells. Recent in vivo and in vitro studies have revealed that the gap junctions of endothelial cells also participate in the promotion of angiogenesis. Pro-angiogenic factors modulate gap junction function and connexin expression in endothelial cells, whereas endothelial connexins are involved in angiogenic tube formation and in the cell migration of endothelial cells. Several mechanisms, including gap junction function-dependent or -independent pathways, have been proposed. In particular, connexins might have the potential to regulate cell mechanics such as cell morphology, cell migration, and cellular stiffness that are dynamically changed during the angiogenic processes. Here, we review the implication for endothelial gap junctions and cellular mechanics in vascular angiogenesis.

Keywords: angiogenesis; cell mechanics; cell migration; cellular stiffness; connexin; gap junction.

Figure 1

Alteration of gap junction function and Cx expression in endothelial cells (ECs) in response to pro-angiogenic stimuli. Vascular endothelial growth factor (VEGF), secreted by cancer cells, is an essential initiator of angiogenesis [82]. Endothelial cells induce internalization and disruption of gap junctions (GJs) formed by Cx43 under VEGF-VEGF-R2 signaling [75,84,85]. The impairment of Cx43 increases proangiogenic plasminogen activator inhibitor-1 (PAI-1) [89] and von Willebrand factor (VWF) [90]. Hypoxic conditions in tumor tissue activate Notch and hypoxia-inducible factors (HIFs) in endothelial cells [73,87,88]. Notch signaling including the nuclear translocation of the notch protein intracellular domain (NICD) induces endothelial cell function and cell mechanics involved in angiogenesis. HIF pathways play an important role in the induction of angiogenic-related genes expression in endothelial cells [73]. Both signaling pathways result in angiogenesis becoming associated with upregulation of Cx37 and Cx40 in endothelial cells [27,88].

Figure 2

Endothelial Cx-dependent regulation of cell migration in angiogenesis. Gap junctions and Cxs regulate cell migration via channel function dependent and independent pathways. (a) Extracellular ATP released by Cx-hemichannels activates P2Y receptors, which trigger cell migration [48]. (b) Gap junction-mediated propagation of calcium waves is required for collective cell migration. (c) The interaction of Cx and gap junction with cytoskeletal proteins or intracellular proteins orchestrates cytoskeletal rearrangement and cell migration [24,116].

Figure 3

Potential role of endothelial cellular stiffness in cell migration. VEGF induces gap junction (GJ) reduction and the sprouting of endothelial cells may result in the stiffening of endothelial cells (ECs) during the sprout initiation phase. Stiff endothelial cells can work as a substrate for attached surrounding cells, whereas, provide a favorable environment for the recruitment of endothelial progenitor cells (EPCs), and then also support adjacent stalk cell proliferation and elongation.