Leptin augments cerebral hemodynamic reserve after three-vessel occlusion: distinct effects on cerebrovascular tone and proliferation in a nonlethal model of hypoperfused rat brain.
The adipocytokine leptin has distinct functions regulating vascular tone, inflammation, and collateral artery growth. Arteriogenesis is an inflammatory process and provides a mechanism to overcome the effects of vascular obstruction. We, therefore, tested the effects of leptin in hypoperfused rat brain (three-vessel occlusion). Systemic leptin administration for 1 week after occlusion surgery increased cerebral hemodynamic reserve similar to granulocyte-macrophage colony-stimulating factor (GM-CSF), as indicated by improved CO(2) reactivity (vehicle 0.53%±0.26% versus leptin 1.05%±0.6% per mm Hg arterial pCO(2), P<0.05). Infusion of microspheres under maximal vasodilation failed to show a positive effect of leptin on cerebral perfusion (vehicle 64.9%±4.5% versus leptin 66.3%±7.0%, occluded/nonoccluded hemisphere). Acute treatment with GM-CSF led to a significant increased CO(2) reactivity and cerebral perfusion (79.2%±8.1% versus 64.9%±4.5%, P<0.05). Vasoconstrictive response of isolated rat carotid artery rings, after phenylephrine was attenuated at 24  hours following preincubation with leptin, was unaffected by removal of endothelium but abrogated by coculture with N-(omega)-nitro-L-arginine methylester, pointing toward an inducible nitric oxide synthase-mediated mechanism. In chronic cerebral hypoperfusion, acute leptin treatment restored the hemodynamic reserve of the cerebral vasculature through its effects on vascular tone, while leaving vascular outward remodeling unaffected. Our results, for the first time, reveal a protective role of leptin on vascular function in hemodynamically compromised brain tissue.
Department of Cardiology and Angiology, Albert Ludwigs University, Freiburg, Germany.
Hans-Joerg
HJ
Busch
Stephan H
SH
Schirmer
Marco
M
Jost
Sylvia
S
van Stijn
Stephan L M
SL
Peters
Jan J
JJ
Piek
Christoph
C
Bode
Ivo R
IR
Buschmann
Guenter
G
Mies
D000818:Animals; D020771:Anterior Cerebral Artery / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002245:Carbon Dioxide / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010101:Oxygen Consumption / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D020769:Posterior Cerebral Artery / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D020738:Leptin; D014662:Vasoconstrictor Agents; D002245:Carbon Dioxide; D010656:Phenylephrine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D052247:Nitric Oxide Synthase Type II