Blockade

of VEGF-A, a potent proangiogenic messenger, is the basis of available therapies for neovascular AMD. The two major pathways by which the RPE produces and secretes VEGF-A are in response to complement (Nozaki, Raisler et al., 2006; Rohrer et al., 2009; Figure 2) and oxidative stress (Pons and Marin-Castaño, 2011; Figure 2). Simply defined, oxidative stress is the oxidation of cellular macromolecules, and the complement system is a set of about 30 proteins that are an important component of the innate immune response to microbes (Bradley et al., 2011). If left unregulated, activation of complement proteins can directly damage host tissue and recruit immune cells to the vicinity of active complement activation. It is presumed that protection against complement is achieved through a variety of complement regulatory molecules that are Pomalidomide expressed in and localize to the retina (Anderson et al., 2010). These primary stresses may act independently to induce angiogenesis, but they also synergize. For example, oxidative stress potentiates complement-induced RPE secretion of VEGF-A (Thurman et al., 2009). Besides VEGF, other directly vasculogenic molecules (i.e.,

that act on endothelial cells; Figure 2) are also secreted by the RPE in response to activated complement (Fukuoka et al., 2003) and oxidative stress (Higgins et al., 2003). Many such RPE-elaborated cytokines have been identified in human and experimental CNV specimens (Amin et al., 1994, Bhutto et al., 2006, Grossniklaus TCL et al., 2002 and Lopez et al., 1996). buy R428 Analysis of human tissue is an important counterpart to information derived from experimental disease models, although it must be noted that these human data are somewhat limited by small sample sizes and also subject to variability introduced in part by technical and logistical challenges of postmortem tissue isolation. Still, the RPE need not be the only source of proangiogenic factors, which could originate from various immune cells or other cell types (Figure 2). Importantly, the focus of the present model is to display

the multiple, redundant pathways via which CNV could be augmented. We emphasize the RPE as a central player in CNV in order to demonstrate two key mechanistic points: (1) The potential for multiple distinct stresses to converge to produce a common (proangiogenic) effect (Figure 2) and (2) the diversity of response molecules produced by the RPE that could drive angiogenesis. Although VEGF-A blockade has dominated CNV treatment, it is reasonable to expect that future endeavors will lead to CNV therapeutics that block other angiogenesis-promoting molecules (Noël et al., 2007). A proinflammatory retinal milieu, which is promoted by RPE response to heterogeneous stresses, appears to be a key modulator of CNV development and progression.