Telmisartan improves hyperlipidemia-induced microvascular dysfunction, cerebral blood flow reduction and impaired remote memory

By using the PCSK9^DY mouse model we have recently demonstrated a link between obesity/hyperlipidemia and cognitive/microvascular dysfunction. We firstly aimed to elucidate whether the AT₁ receptor blocker Telmisartan (TEL) improves cerebral microvascular dysfunction, hippocampal blood flow (HBF) and cognitive dysfunction. We secondly investigated whether a protective TEL effect is attributed to an ACE/AngII/AT₁R-axis or/and Ang(1-7)/ACE2/Mas-axis mediated mechanism, as we recently found that the anti-obesity effect of TEL is also based on a Mas-dependent mechanism, while its anti-atherosclerotic effect is not.

C57BL/6N (wt) or Mas-ko mice received AAV-PCSK9^DY injections (2×10¹¹ VG) or AAV and were fed with Western diet (WD) or chow. Mice were treated with TEL (8 mg/kg) or vehicle. Learning and memory behavior of mice was determined by Barnes maze (BM) tests. HBF was evaluated by ASL-MRI. Brain immunofluorescence was performed on 20μm-thick frozen sections.

Compared to AAV/chow controls, PCSK9^DY/WD wt mice made more "primary errors" on day 17 of BM testing and also showed a less "direct" and quite "random" search strategy to find the escape hole, both indicative of impaired remote memory. Moreover, the HBF was lower in PCSK9^DY/WD than in AAV/chow wt mice. Strikingly, TEL normalized these declines in remote memory and in HBF, despite mice remained hyperlipidemic. However, these protective TEL effects were not observed in Mas-ko mice. The CD31/Col IV ratio was lowered upon PCSK9^DY/WD intervention in hippocampal vessels of both mice strain. TEL normalized this vascular dysfunction in both strains. Evaluation of the CD31/Col IV-stained images additionally revealed more pericytes in both strains upon PCSK9^DY/WD intervention and normalization by TEL.

We conclude that hyperlipidemia impairs remote memory and HBF and both are consolidated by TEL via a Mas-dependent mechanism. We furthermore suggest, that the TEL-dependent normalization of the PCSK9^DY/WD-induced increase of pericytes can contribute to the favorable TEL-effects regarding HBF and memory consolidation, since in pathophysiological conditions such as Alzheimer's disease pericytes have been shown to contribute to vasoconstriction of cerebral capillaries and consequently to a reduction in BF. However, we also suspect that other microvascular effects (which are currently being investigated) must also cause these functional changes, since this pericyte regulation was also observed in the Mas-ko mice.