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.
Highlights
SPONTANEOUS INTRACEREBRAL HEMORRHAGE (ICH) is a high-mortality injury that occurs at a rate of up to 37 per 100,000 in developed countries [40] and accounts for up to 15% of all strokes [13]
The effects of ICH on cerebral artery structure and function can be largely, but not completely, reversed by treatment with the platelet-derived growth factors (PDGFs) receptor antagonist imatinib. These findings support the hypothesis that blood entering the cerebrospinal fluid (CSF) promotes the release of vasoactive factors, which in turn can diffuse throughout the cranial compartment and act on PDGF signaling to help mediate changes in cerebrovascular structure and function that are characteristic of ICH
PDGFs are an important family of growth factors for fibroblasts, vascular smooth muscle, vascular endothelium, and pericytes as well as nonvascular cell types found in the central nervous system including astrocytes, neurons, and Schwann cells [20]
Summary
SPONTANEOUS INTRACEREBRAL HEMORRHAGE (ICH) is a high-mortality injury that occurs at a rate of up to 37 per 100,000 in developed countries [40] and accounts for up to 15% of all strokes [13]. Current evidence strongly implies that phenotypic transformation of cerebrovascular smooth muscle and altered contractile function are prominent consequences of ICH [42, 52], the mechanisms mediating this vascular injury remain unclear. The overall evidence supports the hypothesis that hemorrhagic brain injury promotes the release of multiple vasoactive factors including PDGF and chemically related factors into the CSF, which diffuse throughout the brain’s interstitial compartment and modulate the phenotype of smooth muscle in cerebral arteries. In light of the combined evidence, the present study explored the hypothesis that ICH promotes the local release of vasoactive factors, which in turn diffuse throughout the brain interstitial space and facilitate phenotypic transformation of cerebrovascular smooth muscle remote from the site of initial injury via influence on PDGF receptors. Vascular injury was assessed functionally via myographic measurements of contractility, and structurally by quantitation of contractile protein colocalization, in isolated rat middle cerebral arteries
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