Parathyroid hormone-related protein induction in focal stroke: a neuroprotective vascular peptide.
Parathyroid hormone-related protein (PTHrP) is a multifunctional peptide that enhances blood flow in non-central nervous system (CNS) vascular beds by causing vasodilation. PTHrP expression is induced in non-CNS organs in response to ischemia. Experiments were therefore undertaken to determine whether PTHrP can be induced in brain in response to ischemic injury and whether PTHrP can act locally as a vasodilator in the cerebral vasculature, an effect that could be neuroprotective in the setting of stroke. PTHrP expression was examined by Northern analysis and immunohistochemical staining in male Sprague-Dawley rats subjected to permanent middle cerebral artery occlusion (MCAO). Vasodilatory effects of superfused PTHrP(1-34) on pial arterioles were determined by intravital fluorescence microscopy. Effects of PTHrP(1-34) peptide administration on MCAO infarction size reduction were assessed. PTHrP expression was induced in the ischemic hemisphere as early as 4 h after MCAO and remained elevated for up to 24 h. Increased immunoreactive PTHrP at sites of ischemic tissue injury was located in the cerebral microvessels. Superfusion with PTHrP(1-34) peptide for up to 25 min increased pial arteriolar diameter by 30% in normal animals. In animals with permanent MCAO, PTHrP(1-34) peptide treatment significantly decreased cortical infarct size (-47%). In summary, PTHrP expression increases at sites of ischemic brain injury in the cerebrovasculature. This local increase in PTHrP could be an adaptive response that enhances blood flow to the ischemic brain, thus limiting cell injury.
Funk
Janet L
JL
Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA. jfunk@u.arizona.edu
Migliati
Elton
E
Chen
Guanjie
G
Wei
Hongbing
H
Wilson
Jonathan
J
Downey
Katherine J
KJ
Mullarky
Paul J
PJ
Coull
Bruce M
BM
McDonagh
Paul F
PF
Ritter
Leslie S
LS
D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000601:surgery; D002544:Cerebral Infarction / Q000473:pathology*; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology / Q000601:surgery; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
D016207:Cytokines; D018696:Neuroprotective Agents; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D012333:RNA, Messenger