Angiotensin II mediated pericyte contractility in the spinal cord drives pain development and can be alleviated through local administration of Losartan 

Physiology 2021 (2021) Proc Physiol Soc 48, PC025

Poster Communications: Angiotensin II mediated pericyte contractility in the spinal cord drives pain development and can be alleviated through local administration of Losartan 

Lydia Hardowar1, Philip McTernan1, Dave Bates2, Richard Hulse1

1 Nottingham Trent University, Nottingham, United Kingdom 2 School of Life Sciences, University of Nottingham, NOTTINGHAM, United Kingdom

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Vascular degeneration is a key factor in the development of many neurological diseases. Accumulating evidence implies altered blood brain barrier (BBB) integrity affecting cerebral perfusion in patients of Alzheimer’s, Huntington’s and Amyotrophic lateral sclerosis disease. The increase acknowledgment of the vascular component within the central nervous system (CNS) highlights the importance when considering disease onset and progression. More recently, models of disease within the CNS spinal cord (SC) microvasculature have suggested reduced blood perfusion greatly influencing pain perception. Pericytes, part of the BBB abluminally positioned on small capillaries, demonstrate contractile abilities within cerebral tissue to modulate blood perfusion of nervous tissues. Our preliminary work supports angiotensin II type 1 (AT1) receptor positive pericytes in the SC as a fundamental modulatory component of vasoconstriction. Therefore, this study aims to determine whether Angiotensin II (ANGII), via pericyte AT1 receptor, induces reduced SC blood perfusion through pericyte constriction and whether this impacts upon pain behavioural phenotypes. In vivo studies implied that intrathecal (i.t.) ANGII (100nM, N=6) injected mice develop pain following mechanical and thermal behavioural withdrawal response tests (pre+post i.t.) upto 5hours post-dose compared to vehicle treated group (PBS, N=6) (*P<0.05). To support pericyte activation within the dorsal horn, fluorescently stained paraformaldehyde-fixed SC indicated an increased proportion of constricted CD31-vessels associated with NG2-pericytes 30-minute post i.t. ANGII injection versus vehicle (*P<0.39). Systemic Losartan (AT1 antagonist; 20mg/kg intraperitoneal injection) inhibited ANGII-induced nociceptive behavioural hypersensitivity compared to ANGII (*P<0.0037) 5 hours post-dose, while returning to basal level after 24 hours, however no change was recorded from mechanical behavioural withdrawal response. After repeating this study with local administration of Losartan (10µM i.t.), mechanical pain alleviation occurred 1 hour (N=3; *P<0.022) and 5 hours (N=3; **P<0.009) post-dose versus ANGII i.t. dose alone. These studies highlight an ANGII dependent modulation of pericyte vasocontractility in the SC and pain perception. Furthermore, ANGII induced nociceptive behavioural hypersensitivity can be mechnically and thermally alleviated through local administration of Losartan. 



Where applicable, experiments conform with Society ethical requirements.

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