Background: Hypertension increases the risk for cognitive impairment and promotes vascular and renal inflammation. We tested if immune cell infiltration occurs in the brain during hypertension and if it is associated with cognitive impairment. Building on from this, we also tested whether human amnion epithelial cells that have anti-inflammatory properties can treat hypertension-induced cognitive impairment.

Methods: Male C57Bl/6 mice were administered vehicle, angiotensin II (0.7 mg/kg/d S.C.) or aldosterone (0.72 mg/kg/d S.C.) via osmotic minipumps. A subset of mice also received hydralazine (50 mg/kg) in their drinking water after minipump implantation. We measured systolic blood pressure, markers of inflammation, working memory and transcriptomic changes in the brain. In another cohort, male C57Bl/6 mice were administered vehicle or angiotensin II (0.7 mg/kg/d S.C.). A subset of mice were injected with 106 amnion epithelial cells intravenously after surgery.

Results: Administration of angiotensin II or aldosterone increased blood pressure and promoted blood-brain barrier dysfunction, leukocyte accumulation and impairment of working memory in mice. When co-administered with angiotensin II, hydralazine prevented the development of these changes. In a separate cohort of mice in which angiotensin II-induced changes were first established, intervention with hydralazine lowered blood pressure but did not reverse brain inflammation or cognitive impairment. Angiotensin II infusion altered the transcriptomic profile of the whole brain, as well as specifically within the hippocampus, and co-treatment with hydralazine modulated these changes. Amnion epithelial cells reduced angiotensin II-induced hypertension, cognitive impairment and differential changes in neuroinflammatory genes.

Conclusions: Experimental hypertension leads to brain inflammation and was associated with impaired working memory. Cognitive impairment that develops during hypertension can be inhibited, but not readily reversed, by anti-hypertensive therapy. Amnion epithelial cells could be explored as a potential therapy for neuroinflammation and cognitive impairment during hypertension.

Pericytes are mural cells embedded within the walls of capillaries throughout the body. They play critical roles in regulating blood flow, blood-brain barrier integrity, and vascular repair. After a stroke, the brain undergoes several periods of response to injury, and then recovery, beginning with a hyper-acute phase (0-24h), followed by acute (1-7d), early subacute (7d-3m), late subacute (3-6m) and chronic (>6m) phases. During the hyper-acute phase, pericytes die en masse, particularly in the ischaemic core. In doing so, evidence suggests they die in rigor and therefore constrict capillaries, contributing to the "no-reflow" phenomenon in which microvascular perfusion remains impaired despite successful recanalisation of upstream vessels. Using the intraluminal filament middle cerebral artery occlusion (MCAO) model in mice, we investigate the contribution of pericytes to no-reflow and evaluate novel therapeutic approaches aimed at promoting pericyte relaxation and improving microvascular reperfusion. To support these studies, we have developed an intra-arterial delivery method that enables pericyte-targeted therapeutics to be administered directly to the injured cerebrovasculature immediately following stroke. Our evidence suggests we can precisely deliver therapeutics using this approach, and that they can modulate post-stroke microvascular flow. In parallel, we are investigating the role of pericytes in post-stroke recovery. Beyond their role in acute injury, pericytes may also contribute to endogenous repair processes in recovery phases after stroke. Using the Rose Bengal photothrombotic stroke model in NG2DsRed mice, we have tracked changes in pericytes, blood vessels, and cerebral blood flow within the ischaemic core for up to 28 days after stroke. We found that vascular repair processes are surprisingly active and our findings suggest that recovery of the pericyte population contributes to restoration of the microvascular network. Collectively, these studies identify pericytes as key mediators of both acute microvascular dysfunction and longer-term vascular repair after stroke. By understanding how pericytes influence injury and recovery, we aim to develop targeted therapeutic strategies that improve reperfusion, enhance endogenous repair mechanisms, and ultimately promote recovery following stroke.

BACKGROUND: In neurogenic hypertension, activated macrophages are recruited to the paraventricular nucleus of the hypothalamus (PVN). The chemokine (C-C motif) ligand 2 (CCL2) and its cognate receptor, C-C motif chemokine receptor type 2 (CCR2), play important roles in the activation and recruitment of both macrophages and lymphocytes. Peripheral blockade of CCR2 receptors reduces blood pressure (BP) in rodent models of hypertension. However, it remains unclear whether blockade of CCR2 receptors within the brain can also reduce BP in hypertension.
OBJECTIVES: This study aimed to determine whether blockade of CCR2 receptors in the brain reduces BP in renovascular hypertensive rats.
METHODS: A 2-kidney-1-clip model of renovascular hypertension was used. Following renal artery clipping, rats received a continuous infusion of a selective CCR2 antagonist (RS-102895; 70 μmol/L) into a lateral cerebral ventricle via an osmotic minipump (2.5 μl/hour). BP was monitored by radiotelemetry for 8 weeks.
RESULTS: Blockade of brain CCR2 receptors prevented the increase in BP and macrophage recruitment to the PVN. Treated rats also exhibited significant reductions in the number of activated microglia and neurons in the brain. In contrast, administration of CCL2 (71 nmol/L) into a lateral cerebral ventricle of naïve rats induced macrophage recruitment to the PVN and increased BP.
CONCLUSIONS: These findings demonstrate that, in a renovascular model of hypertension, blockade of brain CCR2 receptors prevents macrophage recruitment, microglial activation, and neuronal activation within the PVN, while reducing BP. The results suggest that macrophage recruitment to the PVN is a critical mechanism in the development of renovascular hypertension.