Chronic Knockdown of the Nucleus of the Solitary Tract AT1 Receptors Increases Blood Inflammatory-Endothelial Progenitor Cell Ratio and Exacerbates Hypertension in the Spontaneously Hypertensive Rat

AT 1 receptor subtype a (AT 1 Ra) expression is increased in the nucleus of the solitary tract (NTS) in spontaneously hypertensive rat (SHR) compared with Wistar Kyoto controls. However, the chronic role of AT 1 Ra in the NTS for cardiovascular control is not well understood. In this study, we investigated the hypothesis that the NTS AT 1 Ra is involved in the neural regulation of the peripheral inflammatory status and linked with hypertension. Transduction of brain neuronal cultures with recombinant adeno-associated virus type 2 (AAV2)-AT 1 R-small hairpin RNA (shRNA) resulted in a 72% decrease in AT 1 Ra mRNA and attenuated angiotensin II–induced increase in extracellular signal–regulated kinase 1/2 phosphorylation and neuronal firing. Specific NTS microinjection of AAV2-AT 1 R-shRNA vector in the SHR resulted in a ≈30 mm Hg increase in the mean arterial pressure compared with control vector–injected animals (Sc-shRNA: 154±4 mm Hg; AT 1 R-shRNA: 183±10 mm Hg) and induced a resetting of the baroreflex control of heart rate to higher mean arterial pressure. In addition, AAV2-AT 1 R-shRNA–treated SHRs exhibited a 74% decrease in circulating endothelial progenitor cells (CD90 + , CD4 − /CD5 − /CD8 − ) and a 300% increase in the circulating inflammatory cells, including CD4 + + CD8 + , CD45 + /3 + T lymphocytes, and macrophages (CD68 + ). As a result, the endothelial progenitor cell/inflammatory cells ratio was decreased by 8- to 15-fold in the AT 1 R-shRNA–treated SHR. However, identical injection of AAV2-AT 1 R-shRNA into the NTS of Wistar Kyoto rats had no effect on mean arterial pressure and inflammatory cells. These observations suggest that increased expression of the AT 1 Ra in SHR NTS may present a counterhypertensive mechanism involving inflammatory/angiogenic cells.