From pathophysiological and mechanistic perspectives, the brains of SHRSP and humans with CSVD show evidence for oxidative stress, endothelial dysfunction, impairment of endothelial nitric oxide synthase (eNOS) with decreased nitric oxide (NO) production, and blood brain barrier (BBB) breakdown [(Schreiber et al., 2013; Mustapha et al., 2019), (Qadri et al., 2003; Rajani et al., 2018; Zhang et al., 2019)]. The gene discussed is NOS3; the disease is endothelial dysfunction.