The biological rationale for incorporating vascular features stems from the fundamental pathophysiology of DME, wherein retinal ischemia and capillary dropout drive compensatory VEGF upregulation; eyes with severe baseline ischemia and reduced perfusion density demonstrate attenuated anti-VEGF response, as the edema mechanism extends beyond VEGF-mediated permeability to include structural microvascular loss [50,51]. Here, VEGFA is linked to ischemia.