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.

AT₁ receptor subtype a (AT₁Ra) 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 AT₁Ra in the NTS for cardiovascular control is not well understood. In this study, we investigated the hypothesis that the NTS AT₁Ra 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)-AT₁R-small hairpin RNA (shRNA) resulted in a 72% decrease in AT₁Ra mRNA and attenuated angiotensin II-induced increase in extracellular signal-regulated kinase 1/2 phosphorylation and neuronal firing. Specific NTS microinjection of AAV2-AT₁R-shRNA vector in the SHR resulted in a ≈30 mmHg increase in the mean arterial pressure compared with control vector-injected animals (Sc-shRNA: 154±4 mm Hg; AT₁R-shRNA: 183±10 mm Hg) and induced a resetting of the baroreflex control of heart rate to higher mean arterial pressure. In addition, AAV2-AT₁R-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 AT₁R-shRNA-treated SHR. However, identical injection of AAV2-AT₁R-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 AT₁Ra in SHR NTS may present a counterhypertensive mechanism involving inflammatory/angiogenic cells. [ABSTRACT FROM AUTHOR]