Abstract 871: Mechanisms Of Vascular T Cell Infiltration In Angiotensin II Dependent Hypertension. Potential Role Of Ccr5-RANTES.
We recently found that the increase in blood pressure, vascular superoxide and aortic hypertrophy caused by chronic low-dose angiotensin II (Ang II) is markedly blunted in RAG-1−/ − mice, which lack both T and B cells. Adoptive transfer of T cells, but not B cell restored these hypertensive phenotypes. The mechanisms whereby T cells promote hypertension and vascular dysfunction remain undefined. We sought to examine mechanisms whereby prolonged Ang II infusion could promote T cells interactions with the vasculature. Two weeks of Ang II infusion (490 ng/kg/min) increased the early activation surface marker CD69 in circulating T cells as well as tissue homing molecules CD44 (16±1% vs 22±1%; p<0.05) and chemokine receptor CCR5 (8±1% vs 14±1%; p<0.02) on CD4+ T cells. Simultaneously, Ang II stimulated a 10 fold increase in CCR5 ligand RANTES mRNA and significantly increased protein expression of ICAM-1 in the aorta. Increased T cell CCR5 and vascular RANTES and ICAM-1 would seem to favor vascular infiltration of T cells. Indeed, Ang II caused a significant infiltration of CD4+ and to a lesser extent CD8+ cells into the aorta as determined by flow cytometry of collagenase-digested vessels: 3.1±0.4×104 vs 1.7±0.5 ×105 cells/aorta; p<0.001) and increased T cell content (15.2±3% vs 24.9±3% of total leukocytes; p<0.02; n=7). These results were confirmed by real time PCR for CD3. Immunohistochemistry for TcR and CD3 showed that angiotensin II stimulated T cells infiltration into the adventitia and periadventitial fat. These regions also showed significant up-regulation of RANTES in Ang II infused animals. Double negative T cells (CD3+ CD4− CD8−), rarely present in blood and recently reported to have pro-inflammatory properties were particularly prevalent in the aorta (30±5%; p<0.01) and Ang II increased their total number by 8-fold. Moreover perivascular T cells expressed high levels of CCR5 (67±3% vs. 8±1% in the blood T cells; p<0.01). Similar T cell infiltration and characteristics was observed in mesenteric vasculature. These data indicate that Ang II activates circulating T cells and promotes their tissue homing via a mechanism dependent on CCR5-RANTES. These mechanisms contribute to hypertension and provide a link between atherosclerosis and hypertension.