Molecular Regulation of Tumor Angiogenesis and Perfusion via Redox Signaling

Angiogenesis is one of several processes that form new blood vessels in higher animals, but it has received the most research attention and popular interest due to its important roles in cancer and wound repair. During early embryogenesis, the first capillary networks form by a process known as vasculogenesis. Cells in the mesoderm differentiate into vascular endothelial cells and spontaneously connect to form a network of tubes known as a vascular plexus15. In contrast to angiogenesis, embryonic vasculogenesis occurs in the absence of blood flow. This primitive vascular network connects to primitive arteries and veins in the embryo, which establishes blood flow in the developing tissue. The directional flow is one signal that can promote differentiation of the vascular plexus into a hierarchical network of arteries, arterioles, capillaries, venules, and veins16. This differentiation process is known as arteriogenesis. Arteriogenesis is also directed by growth factors released from growing nerves in the embryo, which results in the parallel organization of blood vessels and nerved noted by early anatomical studies17. During later development and in adult tissues, angiogenesis plays a major role in new blood vessel formation. Angiogenesis is defined as the formation of new blood vessels from an existing perfused vessel bed. This occurs by sprouting of endothelial cells in the vessel wall, either arterial or venous vessels depending on the soluble factors present18,19, which degrade and invade through the underlying basement membrane barrier and then further invade through the underlying extracellular matrix. As the leading cell moves forward, following endothelial cells proliferate and differentiate to form a luminal space. The leading cell eventually finds another vessel, with which it fuses to establish a patent perfused vessel. Further cycles of this process accompanied by arteriogenesis produces a mature vascular network. In addition to endothelial cells, mature blood vessels require supporting smooth muscle cells. During development, these can be recruited from mesenchymal stem cells or from bone-marrow-derived cells. Arterial vessels develop a thick layer of well organized vascular smooth muscle cells (VSMC) to accommodate the greater hydrostatic pressure in the arterial vasculature. These arterial smooth muscle cells, as will be discussed in greater detail below, also play an important role in adjusting blood flow to specific tissues in response to changing metabolic needs. Veins also have well organized smooth muscle layers, but thinner than those in arteries. The VSMC in capillaries are known as pericytes. In contrast to large vessels, capillary endothelial tubes are not completely covered by pericytes. Rather, the pericytes play important roles in capillary stability and function by secreting factors that regulate endothelial cell function and through direct contact with the adjacent capillary endothelium20. Due to the positive hydrostatic pressure in perfused vessels, a net flow of water, ions, and small solutes constantly occurs across the vessel wall. This is opposed by an osmotic gradient resulting from the lower macromolecular solute concentration in the interstitial space, but nonetheless, net fluid movement occurs from perfused vessels into the underlying tissue. To maintain a constant blood volume, higher animals have a second vascular network, the lymphatics, that return this fluid to the cardiovascular system21. Lymphatics are a blind ended tree of specialized vascular cells, which form by a process known as lymphangiogenesis. It has recently become clear that angiogenesis is not the only mechanism responsible for neovascularization of tumors and wounds in the adult22. In adult tissues, vasculogenesis is mediated by recruitment of circulating endothelial precursor cells that differentiate from hematopoietic stem cells in the bone marrow. These along with specialized monocytic stem cells cooperate to form new vessels at sites of injury and in some cancers. The relative contribution of angiogenesis versus vasculogenesis to tumor neovascularization is currently being actively debated, but it is clear that some tumors depend significantly on bone marrow precursor recruitment, whereas this plays a minimal role in others23,24. Likewise, the role of lymphangiogenesis in tumor growth appears to be quite variable, with a subset of tumors being highly dependent on this process25. This review focuses on the role of redox signaling in angiogenesis and angiogenesis inhibition, but the reader should remain aware that some proangiogenic factors can stimulate vasculogenesis, lymphangiogenesis, and arteriogenesis as well as angiogenesis. Correspondingly, angiogenesis inhibitors can often inhibit more than one of these processes. Therefore, the redox signaling pathways discussed here have been initially defined and are best understood in the context of angiogenesis, but their true function may be more general.