Angiotensin II type 1 receptor activation induces dorsal horn capillary constriction and pain hypersensitivity

Abstract

Vascular disturbance is a key factor in the development of neurological disease, with reduced integrity of the capillary network in the dorsal horn implicated in activation of nociceptive neural circuits and induction of pain states. Pericytes regulate capillary health and tone, with pericyte dysfunction in cerebral tissue associated with neurodegenerative disorders. Our work demonstrates that spinal cord nociceptive processing is influenced by angiotensin II type 1 (AT1) receptor mediated capillary constriction. Intravital imaging of the mouse spinal cord demonstrated angiotensin II induced cessation of spinal cord capillary perfusion. Intrathecal administration of angiotensin II induced narrowing of capillary diameter, which was accompanied by mechanical allodynia and heat hyperalgesia in adult male and female mice. Angiotensin II mediated reduction of spinal cord blood flow and pericyte activation, was prevented by AT1 receptor inhibition via losartan treatment. Losartan prevented angiotensin II induced pain. Integrity of dorsal horn capillary endothelium was protected by co-treatment with losartan preventing angiotensin II induced loss of CD31 immunoreactivity. This investigation demonstrates that AT1 regulates the dorsal horn capillary network and is fundamental in modulating nociceptive processing and perception of pain. Here we identify a novel cellular and mechanistic target for the induction of pain hypersensitivity.

Perspective

Intrathecally delivered Angiotensin II induced mechanical and heat hypersensitivity in male and female mice. Capillary constriction in the dorsal horn was induced by Angiotensin II treatment and led to degeneration of the endothelium. Angiotensin II induced pericyte activation was Angiotensin II type 1 receptor dependent.