Imatinib attenuates cerebrovascular injury and phenotypic transformation after intracerebral hemorrhage in rats

Abstract

This study explored the hypothesis that intracerebral hemorrhage (ICH) promotes release of diffusible factors that can significantly influence the structure and function of cerebral arteries remote from the site of injury, through action on platelet-derived growth factor (PDGF) receptors. Four groups of adult male Sprague-Dawley rats were studied (n = 8 each): 1) sham; 2) sham + 60 mg/kg ip imatinib; 3) ICH (collagenase method); and 4) ICH + 60 mg/kg ip imatinib given 60 min after injury. At 24 h after injury, sham artery passive diameters (+3 mM EGTA) averaged 244 ± 7 µm (at 60 mmHg). ICH significantly increased passive diameters up to 6.4% and decreased compliance up to 42.5%. For both pressure- and potassium-induced contractions, ICH decreased calcium mobilization up to 26.2% and increased myofilament calcium sensitivity up to 48.4%. ICH reduced confocal colocalization of smooth muscle α-actin (αActin) with nonmuscle myosin heavy chain (MHC) and increased its colocalization with smooth muscle MHC, suggesting that ICH promoted contractile differentiation. ICH also enhanced colocalization of myosin light chain kinase (MLCK) with both αActin and regulatory 20-kDa myosin light chain. All effects of ICH on passive diameter, compliance, contractility, and contractile protein colocalization were significantly reduced or absent in arteries from animals treated with imatinib. These findings support the hypothesis that ICH promotes release into the cerebrospinal fluid of vasoactive factors that can diffuse to and promote activation of cerebrovascular PDGF receptors, thereby altering the structure, contractile protein organization, contractility, and smooth muscle phenotype of cerebral arteries remote from the site of hemorrhage.

Acute Treatment With Gleevec Does Not Promote Early Vascular Recovery Following Intracerebral Hemorrhage in Adult Male Rats

“…In the acute stages of ICH (<24 h) numerous mechanisms could contribute to distant modifications of brain vessels (Aronowski and Zhao, 2011;Ren et al, 2014;Schlunk and Greenberg, 2015). Indeed, we have reported on a yet unidentified diffusible factor after ICH that can alter the structure of vessels distant from the injury site that likely modifies vessel morphology as well as function (Pearce et al, 2016).…”

“…More recently we and others have identified that Gleevec antagonism of the platelet-derived growth factor receptor-β (PDGFR-β) on vascular elements. We reported that vascular smooth muscle phenotype is modified after ICH and that Gleevec mitigates this phenotypic switch (Pearce et al, 2016;Yang et al, 2016). Others have also shown that PDGF and its family play an important role in vascular protection using the retina as a model system (He et al, 2014).…”

“…As noted above, we and others have targeted PDGF receptors as a therapeutic option for ICH using Gleevec (imatinib mesylate) (Ma et al, 2011;Pearce et al, 2016;Yang et al, 2016). We found that Gleevec treatment following ICH blunts the phenotypic transformation of smooth muscle surrounding arteries (Pearce et al, 2016), reduced BBB disruption leading to improved outcomes (Ma et al, 2011) and mitigated plasmin induced vascular inflammation (Yang et al, 2016). Many of the beneficial effects of Gleevec were found to occur acutely (<24 h) with long term improvements but the direct effects on vascular morphology have not been reported upon.…”

“…ICH was induced using the Bacterial Collagenase injection model as previously described (Pearce et al, 2016). Rats underwent isoflurane anesthesia (4% induction with 2% maintenance in 70% medical air and 30% O 2 ) and then were secured prone onto a stereotactic frame (David Kopf Instruments, Tujunga, CA, United States).…”

“…While neuroinflammation and other secondary injury cascades in the context of ICH have been well studied previously (Yang et al, 2016), little has been reported on the how ICH modifies cerebrovascular integrity and morphology. We have previously reported that ICH results in a modified cerebral vascular smooth muscle phenotype (Pearce et al, 2016). However, the morphological features of the injured cerebrovasculature including integrity of the neurovascular unit are critical features that are poorly understood.…”