Precapillary arteriolar and capillary pericytes contribute to the regulation of cerebral blood flow (CBF) and blood-brain barrier (BBB) integrity, both of which are critical for brain health. Diabetes causes a decrease in microvascular pericytes. Since diabetes increases the risk of PSCI, our first goal was to investigate the impact of diabetes on pericyte phenotype after stroke. Given that endothelin-1 (ET-1) mediates pericyte constriction and senescence via the ETA receptors (ETAR), the second goal was to assess ETAR expression after stroke and the impact of ETAR inhibition on pericyte phenotype. Methods and Results: We used tissue sections from our rodent brain bank. Pericyte numbers and surface area (SA) were assessed by immunohistochemistry using CD13 and Atp13a5 pericyte markers. CD13+/high aSMA and Atp13a5-expressing cells were classified as contractile precapillary arteriolar and capillary pericytes, respectively. The first set of specimens was from diabetic male rats that were subjected to sham or 60-min transient middle cerebral artery occlusion (tMCAO) surgery and followed for 2 weeks. Stroke caused an increase in the number of CD13+ cells (3.3 ± 0.5 vs 7.5 ± 1.6, p<0.04) in diabetic rats (n=5/group). The second set was from control and diabetic rats that were subjected to tMCAO and followed for 8 weeks. CD13 staining intensity (0.3 ± 0.01 vs 3.7 ± 1.1, p=0.04), CD13+ volume (15.7 ± 9.1 vs 418.3 ± 131.3, p=0.03), and number of CD13+ cells (7.2 ± 1.3 vs 61.1 ± 17.3, p=0.03, n=5-6) were greater in diabetic rats. There was a trend for lower Atp13a5 signal in diabetic rats (0.5 ± 0.1 vs 0.2 ± 0.03, p=0.06). Stroke increased the ETAR signal that colocalized with CD13 (18.7 ± 1.3 vs 59.9 ± 7.2, p=0.005). In the third set, diabetic rats were subjected to sham or tMCAO surgery and treated with intranasal ETAR antagonist BQ123 (Day 3-17) and followed for 8 weeks. Contractile precapillary pericytes were increased after stroke (15.7 ± 4.9 vs 60.3 ± 6.6, p=0.001) and BQ123 treatment prevented this increase (29.3 ± 7.7, p=0.04). Conclusions: Stroke-mediated increase in contractile precapillary arteriolar pericytes and increased ETAR expression in diabetic rats may dysregulate CBF after stroke. Stroke-mediated decrease in capillary pericytes may contribute to the disruption of the BBB. Inhibition of ETAR after stroke may be a therapeutic strategy to prevent pathological alterations in pericyte phenotype that contribute to the development of PSCI.
Edgerton-Fulton et al. (Thu,) studied this question.