Therapeutic Induction of Arteriogenesis in Hypoperfused Rat Brain Via Granulocyte-Macrophage Colony-Stimulating Factor

Abstract

Background-Colony-stimulating factors (CSFs) have been shown to effectively induce arteriogenesis in the hindlimb.Moreover, clinical trials demonstrated positive effects of CSFs on arteriogenesis in patients with coronary artery disease. However, patients with cerebrovascular disease have not yet profited from treatments aimed at the growth of brain vessels. Thus far, angiogenesis studies have failed to demonstrate improvement of stroke outcome. Arteriogenesis differs from angiogenesis in that it substitutes arterial collaterals for the occluded artery. Methods and Results-We tested in a novel brain arteriogenesis rat model (occlusion of vertebral plus left carotid artery ) the application of CSFs or saline over 7 or 21 days. On 3-VO postmortem, latex perfusion demonstrated a timeand treatment-dependent arteriogenesis of the posterior cerebral artery (PCA). In saline-treated animals, the PCA diameter increased by 39%; in granulocyte-macrophage (GM)-CSF-treated animals, this increase was significantly faster (72% after 1 week). Functionally, saline-treated animals exhibited a decline of CO 2 reactivity (mm Hg) from 1.48% to 0.1% compared with GM-CSF-treated animals (1.43% arterial pCO 2 change after 1 week). This difference remained significant after 3 weeks. This functional improvement correlated with increased numbers of CD68-positive macrophages in histological sections of the PCA in GM-CSF-treated animals and only a few macrophages in saline-treated animals. Conclusions-To the best of our knowledge, this is the first report of stimulation of arteriogenesis in the brain. Key Words: arteries Ⅲ stroke Ⅲ cerebrovascular circulation Ⅲ drugs T he adaptive proliferation of preexisting collateral pathways (arteriogenesis) is an effective biological rescue system against detrimental effects of arterial stenosis. We have recently demonstrated that occlusion of the left carotid artery (CA) and both vertebral arteries induced a significant redistribution of blood flow via the left posterior cerebral artery (PCA), which increased its diameter 2-fold. Importantly, the induced hemispheric hypoperfusion was not severe enough to produce expression of the angiogenic factor VEGF (vascular endothelial growth factor) or histological injury. On the functional level, we demonstrated that this adaptive arteriogenesis led to a significant improvement of the hemodynamic capacity of the hypoperfused brain. Thus, we proposed a novel concept of brain protection by arteriogenesis: collateral artery growth as a means to prevent cerebral ischemia during progressing cerebrovascular disease. 1 Several experimental studies have shown that the speed of arteriogenesis is not limited to its natural time course. The infusion of CC chemokines (monocyte chemotactic protein-1), 2 fibroblast growth factors, 3 or granulocyte-macrophage colony-stimulating factor (GM-CSF) into the peripheral or coronary collateral circulation led to a significant increase in collateral conductance compared with untreated animals. The proarteriogenic effect of the latter ...

Endothelial Progenitor Cells Augment Collateralization and Hemodynamic Rescue in a Model of Chronic Cerebral Ischemia

“…Some previous studies evaluated arteriogenic effects after longer time intervals-for example, after systemic administration of growth factorssuggesting a long-term recovery effect with the requirement of a longer time interval to permit sufficient structural remodeling. 4,5 Other studies, however, also demonstrated structural changes as soon as 1 week after conductance vessel occlusion 27,28 and recent findings from our group on vascular remodeling in a mouse model of chronic cerebral hypoperfusion are in line with these results. 19 Next to the structural remodeling, functional improvement of the vasodilation response could additionally contribute to the higher CVRC after treatment with e-EPC.…”

“…20 In the brain, therapeutic stimulation of collateral vessel growth at the level of the basal vasculature was initially reported by Buschmann et al and later confirmed by our group. 4,5 Overall, treatment with e-EPC but not e-EPDC compared favorably with these results and led to a significant increase of the ICA and MCA vessel diameters in the anterior circulation. This, together with the positive remodeling of the leptomeningeal and microcirculatory vasculature in e-EPCtreated animals (see below) could account for their improved CVRC and reduced need for compensational cross-flow via the P1 segment, which serves as the natural conduit between the anterior and posterior circulation.…”

“…Arteriogenesis, however, is characterized as the positive outgrowth of preexisting collaterals at the level of the conductance or resistance vasculature, which coincides with an augmentation of collateral flow. 4,5,19 Against this background, we investigated EPC e-EPC treatment of cerebral hemodynamic compromise N Hecht et al as a novel treatment modality for chronic cerebral hypoperfusion because EPC secrete various proangiogenic growth factors, [20][21][22] which may be beneficial in chronic steno-occlusive cerebrovascular disease where neovascularization in terms of collateral vessel growth is required in regions apart from the ischemic tissue. Moreover, EPC are characterized by high plasticity and promigratory activity with the potential for active incorporation into a developing vasculature.…”

Granulocyte-macrophage colony-stimulating factor-induced arteriogenesis reduces energy failure in hemodynamic stroke

“…The functional significance of brain arteriogenesis is reflected by an improvement of the hemodynamic reserve, as demonstrated by the gradual recovery of CO 2 reactivity, which, shortly after 3-VO, is completely suppressed (1). Under conditions of permanently increased vascular shear stress, arteriogenesis proceeds spontaneously, but the speed of vascular growth can be markedly accelerated by various cytokines, notably by GM-CSF (8).…”

“…In the 3-VO model, GM-CSF also markedly accelerated arteriogenesis, as reflected by the faster expansion of the diameter of the posterior cerebral artery and normalization of the hemodynamic reserve within 1 week after onset of treatment (8). GM-CSF-induced arteriogenesis may therefore protect the brain against stroke by improvement of collateral blood supply.…”