Polypoidal Choroidal Vasculopathy: From Clinicopathological and Molecular Perspectives.

Polypoidal choroidal vasculopathy (PCV) causes a severe visual impairment in patients with neovascular age-related macular degeneration (nAMD). Currently, PCV is classified as a subtype or variant of type 1 macular neovascularization (MNV), based on the neovascular characteristics of the lesions. These include both polypoidal lesion(s) (PLs) and branching neovascular network (BNN) that develops within Bruch's membrane and is located beneath the basal lamina of the retinal pigment epithelium (RPE). Effective treatments for PCV remain limited, despite the variable efficacy of anti-vascular endothelial growth factor (VEGF) drugs in regressing PLs. A key contributing factor is the incomplete understanding of the disease mechanisms, which highlights the necessity for reliable animal models to facilitate further research. Thus, it is of great importance to comprehensively understand this complex disease from multiple perspectives, including clinical manifestations, multimodal imaging, and clinicopathological features. This study aims to elucidate the complexities of PCV through an integrated analysis of its clinical characteristics, pathological features, and molecular mechanisms. In fact, both PLs and BNN are the neovascular lesions as evidenced by both optical coherence tomography angiography (OCTA) and clinicopathological studies. However, several distinguishing features exist between PLs and BNN, including lesion location, cellular component, and vascular maturity. Three-dimensional OCTA reconstruction demonstrated the anteroposterior separation between the PLs and BNN, and the presence of the internal microvascular architecture with some small nodules within PLs. Importantly, the clinicopathological analysis demonstrated a marked incomplete coverage of mural cells, including no pericyte coverage in PLs and relatively less coverage of vascular smooth muscle cells in BNN based on the clinicopathological analysis. The incomplete coverage of mural cells might be due to the increased expression of angiopoietin 2 (Ang-2), resulting in the loss or dropout of mural cells via the integrin-mediated signaling pathway. Regressing PLs and promoting BNN maturity through various approaches might provide an optimal treatment strategy for PCV management. However, a comprehensive understanding of the complex mechanisms of PCV merits further investigation for better management of this refractory disease.