Human amnion epithelial cells reduces hypertension induced vascular stiffening and cognitive impairment

Abstract

Introduction: Vascular stiffening and inflammation are hallmarks of hypertension and contribute to the development of cardiovascular disease and cognitive impairment. Current treatments for hypertension may reduce blood pressure but do not target the associated pathological changes and end-organ damage. It is also inconclusive from clinical trials whether anti-hypertensive medication can improve cognitive impairment. Cell therapy has great therapeutic potential as unlike single pharmacological agents, cells can deliver multiple mediators which could more effectively target complex disease mechanisms. Human amnion epithelial cells (AECs) have many properties (eg. anti-inflammatory, anti-fibrotic, and immunologically inert) that make them attractive candidates for a cell-based therapy for vascular and brain pathology. Aim: To test the potential of AECs to treat vascular and brain pathology in angiotensin II-induced hypertension. Methods. Male C57Bl6 mice (8-12 weeks) were administered vehicle (saline; n=35) or angiotensin II (0.7 mg/kg/d, n=37) for 14 d via an osmotic minipump. After minipump implantation, a subset of mice were injected with 10 6 of AECs intravenously. Systolic blood pressure was measured using tail-cuff; pulse wave velocity was measured using ultrasound, inflammation was assessed using flow cytometry and RNA sequencing, markers of fibrosis using quantitative PCR and cognitive function using novel object recognition test. Results: Angiotensin II infusion increased blood pressure and aortic pulse wave velocity (n=6-7, P<0.05). In aorta, angiotensin II promoted accumulation of leukocytes, specifically macrophages and monocytes, which were elevated by ~3-fold compared to vehicle-infused mice (n=9-11, P<0.05). Angiotensin II also increased aortic mRNA expression of collagen type 1 alpha 1 ( Col1a1) by ~4-fold and collagen type 5 alpha 1 ( Col5a1) by ~7-fold compared to vehicle (n=6-8, P<0.05). Co-administration of AECs limited the development of hypertension and aortic stiffening by angiotensin II (185±5 mmHg vs 165±4 mmHg; n=9-11, P<0.05), as well as the aortic infiltration of macrophages and monocytes (n=9-11, P<0.05) and expression of Col1a1 and Col5a1 (n=6-8, P<0.05). Infusion with angiotensin II also impaired memory which was improved by AECs (n=7-9, P<0.05). RNA sequencing revealed that in the brain, angiotensin II increased expression of genes involved in inflammation ( Ptcra, Blk, Bpifb1), fibrosis ( Col6a5) and apoptosis ( Fas) and co-administration of AECs caused downregulation of these genes. Conclusions: Intravenous administration of AECs blunted angiotensin II-induced hypertension, aortic stiffening, inflammation and cognitive impairment in male mice. The beneficial effects of AECs on blood pressure and aortic stiffening could have contributed to the improvement in cognition. This study suggests that AECs or their cellular products could be explored as treatments for vascular and brain pathology during hypertension. La Trobe University Start Up grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.