Perivascular Adipose Tissue in Vascular Function: Does Locally Synthesized Angiotensinogen Play a Role?

Abstract

In recent years, perivascular adipose tissue (PVAT) research has gained special attention in an effort to understand its involvement in vascular function. PVAT is recognized as an important endocrine organ that secretes procontractile and anticontractile factors, including components of the renin-angiotensin-aldosterone system, particularly angiotensinogen (AGT). This review critically addresses the occurrence of AGT in PVAT, its release into the blood stream, and its contribution to the generation and effects of angiotensins (notably angiotensin-(1-7) and angiotensin II) in the vascular wall. It describes that the introduction of transgenic animals, expressing AGT at 0, 1, or more specific location(s), combined with the careful measurement of angiotensins, has revealed that the assumption that PVAT independently generates angiotensins from locally synthesized AGT is incorrect. Indeed, selective deletion of AGT from adipocytes did not lower circulating AGT, neither under a control diet nor under a high-fat diet, and only liver-specific AGT deletion resulted in the disappearance of AGT from blood plasma and adipose tissue. An entirely novel scenario therefore develops, supporting local angiotensin generation in PVAT that depends on the uptake of both AGT and renin from blood, in addition to the possibility that circulating angiotensins exert vascular effects. The review ends with a summary of where we stand now and recommendations for future research.

Targeting Angiotensinogen With N -Acetylgalactosamine–Conjugated Small Interfering RNA to Reduce Blood Pressure

“…Apparently, therefore, despite local AGT expression, the actual AGT protein at these extrahepatic sites is liver derived. Given these findings, which coincide with observations in transgenic animals genetically lacking kidney or adipose tissue AGT, 20,[49][50][51][52] currently, mechanisms are being investigated that might explain AGT uptake from blood. Here, an important newly identified candidate is the megalin receptor.…”

Conventional Vasopressor and Vasopressor‐Sparing Strategies to Counteract the Blood Pressure–Lowering Effect of Small Interfering RNA Targeting Angiotensinogen

“…This confirms that also in mice, eWAT angiotensinogen is predominantly derived from the liver, at least under normal circumstances. 25 Fludrocortisone increased blood pressure similarly in hepatocyte angiotensinogen‐deficient and control mice, but was unable to upregulate plasma angiotensinogen and even reduced plasma angiotensinogen concentrations in control mice, in spite of upregulated Agt mRNA and angiotensinogen protein abundance in eWAT in both strains. In hepatocyte angiotensinogen‐deficient mice, the increase in eWAT after fludrocortisone was of similar magnitude as that in the siRNA‐treated rats.…”

Adipokines regulate mesenchymal stem cell osteogenic differentiation

“…Not all human adipokines have been identified, but the current literature has revealed that the surface adipose tissue secretes more than 600 factors or proteins involving many processes of human pathophysiology[ 130 ]. There are many types of adipokines, including cytokines[ 22 ], fibrinolysin[ 44 ], complement and related proteins[ 49 ], enzymes[ 121 ], lipid transport systems[ 116 ], endocannabinoids[ 131 ], and angiotensinogen[ 132 ] (Table 1 ).…”