Leptin augments cerebral hemodynamic reserve after three-vessel occlusion: distinct effects on cerebrovascular tone and proliferation in a nonlethal model of hypoperfused rat brain

Abstract

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.

Figure 1

Cerebral angioarchitecture. Visualization of the cerebral angioarchitecture using the latex method after maximal vasodilation. Dorsal view of brains investigated 1 week after three-vessel occlusion (3-VO) in vehicle- and leptin-treated animals. Leptin treatment leads to a moderate but not significant enlargement of ipsilateral PCA (arrows) compared with vehicle-treated animals.

Figure 2

Vasoreactivity after leptin incubation ex-vivo. Carotid rings were preincubated with leptin for 24 hours, and cumulative concentration response curves were calculated for the contractile reaction toward phenylephrine. (A) Note the delay in the phenylephrine-induced contractile response after 24-hour leptin incubation. (B) -NAME (N-(omega)-nitro--arginine methylester) treatment of endothelium-removed carotid artery rings completely abrogated the effects of leptin incubation, pointing toward an inducible nitric oxide synthase-mediated mechanism.