Impaired myogenic response of MCA elevates transmission of pressure to penetrating arterioles and contributes to cerebral vascular disease in aging hypertensive FHH rats

We recently identified a K572Q mutation in Add3 in FHH rats. The present study examined whether it contributes to cerebral vascular dysfunction in aging and after the development of hypertension. The expression of Add3 is lower in FHH than in FHH.1 BN rats. The inner diameter of MCA decreased by 80 ± 2 % and 71 ± 4% in FHH.1 BN and FHH.Add3 transgenic rats, respectively, when perfusion pressure was increased from 40 to 140 mmHg. The pressure in terminal pial arteries was greatly increased from 37 ± 1 to 63 ± 4 mmHg in FHH rats when MAP was increased from 100 to 160 mmHg but was unchanged (34 ± 1 to 36 ± 1 mmHg) in FHH.1 BN rats. The inner diameters of capillaries in the deep cortex were markedly larger (8 ± 2 vs. 22 ± 1 μm) and capillary density was reduced (15 ± 0.4% vs. 8 ± 2%) in FHH than in FHH.1 BN rats. The expression of phosphorylated‐ERK1/2 and phosphorylated‐PKC was reduced in the brain of FHH than FHH.1 BN rats. CBF rose by 99 ± 7%, 64 ± 5% and 42 ± 4% in FHH, FHH.1 BN and FHH.Add3 rats, respectively, when MAP was increased from 100 to 190 mmHg, demonstrating that the impaired autoregulation of CBF in FHH rats was rescued by introduction of wildtype Add3. BBB leakage was greater in FHH rats than FHH.1 BN and FHH.Add3 rats after induction of DOCA/salt hypertension. Hypertensive FHH rats exhibited marked neurodegeneration and vascular remodeling of the neocortex and hippocampus with a 33% reduction in the density and size of neurons relative to FHH.1 BN and FHH.Add3 rats. Gap junctions between endothelial cells were larger in hypertensive FHH rats with neuronal, mitochondrial and myelin degeneration in the vacuolated area near leaky capillaries. The hypertensive FHH rats took 2.5 times longer to escape from an eight‐arm water maze than hypertensive FHH.1 BN rats suggesting spatial learning and memory dysfunction. These findings suggest that the K572Q mutation in FHH rats decreases the expression and activity of Add3 which is involved in phosphorylation of PKC and ERK1/2. This contributes to the impaired myogenic response and autoregulation of CBF, therefore elevating the transmission of pressure in penetrating arterioles that ultimately promotes loss of cerebral capillaries, BBB leakage and neurodegeneration, which may contribute to vascular cognitive impairments with hypertension and age. Support or Funding Information This study was supported by grants HL36279 and DK104184 (RJR) from the National Institutes of Health.