Perivascular adipose tissue plasticity in response to angiotensin II

Most blood vessels are surrounded with perivascular adipose tissue (PVAT), which is a unique adipose tissue that plays critical roles in vascular physiology and pathophysiology. PVAT displays regional differences that impact vascular homeostasis. Angiotensin II (Ang II) is the main biological active effector of the renin-angiotensin-aldosterone system (RAAS), which has been extensively studied in the vascular biology. However, the effects of Ang II on PVAT are limited explored and remain to be elucidated. In this study, we systematically investigated the regional heterogeneity of three portions of aortic PVAT, i.e., ascending thoracic aortic PVAT (ATA-PVAT), descending thoracic aortic PVAT (DTA-PVAT), and abdominal aortic PVAT (AA-PVAT), and their responses to 7-day Ang II infusion using RNA sequencing. We found that AA-PVAT is clearly distinguished from both ATA-PVAT and DTA-PVAT, with significantly down-regulated oxidative phosphorylation and up-regulated inflammatory response pathways. Furthermore, AA-PVAT expressed lower levels of brown adipocyte marker genes, such as Ucp1, Cidea, Cox8b, Dio2 and Pgc1α, but expressed higher levels of proinflammatory genes, such as Ccl2, Il1β and Tnfα, and components of the RAAS, including Agt, Ace and Agtr1α. Ang II infusion significantly down-regulated oxidative phosphorylation in all aortic PVAT and significantly up-regulated inflammatory response specifically in ATA-PVAT and DTA-PVAT. Moreover, ATA-PVAT was most responsive to Ang II induced inflammation. We further used a mitoNEET (a.k.a. CDGSH iron sulfur domain 1 protein) transgenic mouse model that exhibited a more brown adipose tissue (BAT)-like phenotype in aortic PVAT, as indicated by elevated expression levels of brown adipocyte marker genes, and confirmed that a more BAT-like phenotype of aortic PVAT could counterbalance Ang II induced inflammatory and oxidative effects. Wild type (WT) C57BL/6J mice were from the Jackson Laboratory (stock number 000664), the mitoNEET transgenic mice (mitoNEET-Tg) in a C57BL/6J background were constructed to express human mitoNEET driven by the mouse Ucp1 promoter, as previously described [24]. The mice were housed in ventilated cage at 22°C with 12 h/12 h light/dark cycle and were maintained on a standard chow diet and tap water ad libitum. For Ang II infusion experiment, 8- to 12-week-old mice were subcutaneously implanted with osmotic mini-pumps (Alzet, Model #2004) carrying Ang II (1000 ng/kg/min, BACHEM) or saline (as control) for 7 days. Then the mice were sacrificed and the aortic PVAT were dissected.