Phenotypic modulation of smooth muscle cells and vascular remodeling in intraparenchymal small cerebral arteries after canine experimental subarachnoid hemorrhage

Ohkuma, Hiroki; Suzuki, Shigeharu; Ogane, Kazumi

doi:10.1016/s0304-3940(03)00464-6

Cited by 20 publications

(16 citation statements)

References 12 publications

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“…A previous study indicated that MMP-9 was expressed in the vascular wall and the co-staining for vascular smooth muscle cells showed that the MMP-9 expression localized to the vascular smooth muscle cells after SAH 8 . The switch of vascular smooth muscle phenotype may not markedly affect the size or function of the large arteries in the previous study 1, 31 , but some studies reported that unbalanced contractile/synthetic vascular smooth muscle phenotype affected the size of the cerebral arteries and aggravated brain swelling and brain edema 29,30,32 . It is presumed that due to the limited two or three layers of smooth muscle cells in smaller arteries, vascular smooth muscle phenotype change causes the loss of small arteries vascular tone and affects BBB and autoregualtion.…”

Section: Discussionmentioning

confidence: 79%

“…Previous studies suggested that vascular smooth muscle phenotypic transformation may be caused by local tissue pressure or stretch increases and by blood metabolic products after SAH 10, 28 . Contractile vascular smooth muscle contributed to vascular tone and regulation of blood vessel diameter and blood flow distribution 29 . Vascular smooth muscle phenotypic transformation from contractile to synthetic phenotype may result in decreasing auto regulatory capacity and regional cerebral blood flow to enhance brain swelling and brain edema 28, 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Contractile vascular smooth muscle contributed to vascular tone and regulation of blood vessel diameter and blood flow distribution 29 . Vascular smooth muscle phenotypic transformation from contractile to synthetic phenotype may result in decreasing auto regulatory capacity and regional cerebral blood flow to enhance brain swelling and brain edema 28, 29 . One of the mechanisms of the BBB breakdown following SAH is the proteolysis of tight junction proteins by matrix metallo proteinases (MMPs) 30 .…”

Section: Discussionmentioning

confidence: 99%

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Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats

Zhang

Yang

et al. 2016

Stroke

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Background and Purpose Recombinant Osteopontin (rOPN) has been reported to be neuroprotective in stroke animal models. The purpose of this study is to investigate a potential role and mechanism of nasal administration of rOPN on preserving the vascular smooth muscle phenotype in early brain injury after SAH. Methods One hundred and ninety-two male adult Sprague-Dawley rats were used. The SAH model was induced by endovascular perforation. Integrin-linked kinase (ILK) siRNA was intracerebroventricularly injected 48 hours before SAH. The integrin receptor antagonist GRGDSP, FAK inhibitor Fib-14 and Rac-1 inhibitor NSC23766 were administered 1 hour before SAH induction. rOPN was administered via the intracerebroventricular and nasal route after SAH. SAH grade, neurological scores, brain water content, brain swelling, hematoxylin and eosin staining, India ink angiography, Western blots, and immunofluorescence were used to study the mechanisms of rOPN on the vascular smooth muscle phenotypic transformation. Results The marker protein of vascular smooth muscle phenotypic transformation alpha-SMA decreased and SMemb increased significantly at 24 and 72 hours in the cerebral arteries after SAH. rOPN prevented changes of alpha-SMA and SMemb, and significantly alleviated neurobehavioral dysfunction, increased the cross-section area and the lumen diameter of the cerebral arteries, reduced brain water content and brain swelling and improved the wall thickness of cerebral arteries. These effects of rOPN were abolished by GRGDSP, ILK siRNA and NSC23766. Intranasal application of rOPN at 3 hrs after SAH also reduced neurological deficits. Conclusions rOPN prevented the vascular smooth muscle phenotypic transformation and improved the neurological outcome, which was possibly mediated by the integrin receptor/ILK/Rac-1 pathway.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats

Zhang

Yang

et al. 2016

Stroke

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“…Patterns of vascular remodeling vary greatly in relation to vessel type, size, age, and anatomical location (31,60) and are particularly important during periods of rapid growth, such as those occurring in a mother and fetus during pregnancy and following birth (31,46). Vascular remodeling is also a driving influence of many pathophysiological processes, particularly those induced by chronic hypoxia (23,68), ischemia (41), hypertension (66), and atherosclerosis (50).…”

mentioning

confidence: 99%

Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries

Hubbell

Semotiuk

Thorpe

et al. 2012

American Journal of Physiology-Cell Physiology

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Hubbell MC, Semotiuk AJ, Thorpe RB, Adeoye OO, Butler SM, Williams JM, Khorram O, Pearce WJ. Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries. Am J Physiol Cell Physiol 303: C1090 -C1103, 2012. First published September 19, 2012 doi:10.1152/ajpcell.00408.2011.-Chronic hypoxia increases vascular endothelial growth factor (VEGF) and thereby promotes angiogenesis. The present study explores the hypothesis that hypoxic increases in VEGF also remodel artery wall structure and contractility through phenotypic transformation of smooth muscle. Pregnant and nonpregnant ewes were maintained at sea level (normoxia) or 3,820 m (hypoxia) for the final 110 days of gestation. Common carotid arteries harvested from term fetal lambs and nonpregnant adults were denuded of endothelium and studied in vitro. Stretch-dependent contractile stresses were 32 and 77% of normoxic values in hypoxic fetal and adult arteries. Hypoxic hypocontractility was coupled with increased abundance of nonmuscle myosin heavy chain (NM-MHC) in fetal (ϩ37%) and adult (ϩ119%) arteries. Conversely, hypoxia decreased smooth muscle MHC (SM-MHC) abundance by 40% in fetal arteries but increased it 123% in adult arteries. Hypoxia decreased colocalization of NM-MHC with smooth muscle ␣-actin (SM-␣A) in fetal arteries and decreased colocalization of SM-MHC with SM-␣A in adult arteries. Organ culture with physiological concentrations (3 ng/ml) of VEGF-A165 similarly depressed stretch-dependent stresses to 37 and 49% of control fetal and adult values. The VEGF receptor antagonist vatalanib ablated VEGF's effects in adult but not fetal arteries, suggesting age-dependent VEGF receptor signaling. VEGF replicated hypoxic decreases in colocalization of NM-MHC with SM-␣A in fetal arteries and decreases in colocalization of SM-MHC with SM-␣A in adult arteries. These results suggest that hypoxic increases in VEGF not only promote angiogenesis but may also help mediate hypoxic arterial remodeling through age-dependent changes in smooth muscle phenotype and contractility.

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“…Prior investigations have produced conflicting results with some studies indicating that vasospasm is completely reversible with adequate doses of pharmacological vasodilators (22,29) and others suggesting that vasospasm is due to a temporarily irreversible structural change in the arterial wall (44). The latter process would suggest the presence of some degree of arterial remodeling (31). Interpretation of prior studies is compromised by lack of documentation that vasospasm actually occurred as well as the use of models that do not produce severe delayed vasospasm (5) or that use systemic arteries in which the perivascular inflammatory and fibrotic reaction is markedly different from that occurring intracranially (13,32).…”

mentioning

confidence: 99%

Calcium sensitivity of vasospastic basilar artery after experimental subarachnoid hemorrhage

Macdonald

Zhang

Takahashi

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Arteries that develop vasospasm after subarachnoid hemorrhage (SAH) may have altered contractility and compliance. Whether these changes are due to alterations in the smooth muscle cells or the arterial wall extracellular matrix is unknown. This study elucidated the location of such changes and determined the calcium sensitivity of vasospastic arteries. Dogs were placed under general anesthesia and underwent creation of SAH using the double-hemorrhage model. Vasospasm was assessed by angiography performed before and 4, 7, or 21 days after SAH. Basilar arteries were excised from SAH or control dogs (n = 8-52 arterial rings from 2-9 dogs per measurement) and studied under isometric tension in vitro before and after permeabilization of smooth muscle with alpha-toxin. Endothelium was removed from all arteries. Vasospastic arteries demonstrated significantly reduced contractility to KCl with a shift in the EC(50) toward reduced sensitivity to KCl 4 and 7 days after SAH (P < 0.05, ANOVA). There was reduced compliance that persisted after permeabilization (P < 0.05, ANOVA). Calcium sensitivity was decreased during vasospasm 4 and 7 days after SAH, as assessed in permeabilized arteries and in those contracted with BAY K 8644 in the presence of different concentrations of extracellular calcium (P < 0.05, ANOVA). Depolymerization of actin with cytochalasin D abolished contractions to KCl but failed to alter arterial compliance. In conclusion, it is shown for the first time that calcium sensitivity is decreased during vasospasm after SAH in dogs, suggesting that other mechanisms are involved in maintaining the contraction. Reduced compliance seems to be due to an alteration in the arterial wall extracellullar matrix rather than the smooth muscle cells themselves because it cannot be alleviated by depolymerization of smooth muscle actin.

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Phenotypic modulation of smooth muscle cells and vascular remodeling in intraparenchymal small cerebral arteries after canine experimental subarachnoid hemorrhage

Cited by 20 publications

References 12 publications

Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats

Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats

Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries

Calcium sensitivity of vasospastic basilar artery after experimental subarachnoid hemorrhage

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