Dataset Information

Sex Differences in the Cerebral Collateral Circulation.

ABSTRACT: Premenopausal women and intact female rodents sustain smaller cerebral infarctions than males. Several sex-dependent differences have been identified as potential contributors, but many questions remain unanswered. Mice exhibit wide variation in native collateral number and diameter (collateral extent) that is dependent on differences in genetic background, aging, and other comorbidities and that contributes to their also-wide differences in infarct volume. Likewise, variation in infarct volume correlates with differences in collateral-dependent blood flow in patients with acute ischemic stroke. We examined whether extent of pial collateral arterioles and posterior communicating collateral arteries (PComAs) differ depending on sex in young, aged, obese, hypertensive, and genetically different mice. We combined new data with meta-analysis of our previously published data. Females of C57BL/6J (B6) and BALB/cByJ (BC) strains sustained smaller infarctions than males after permanent MCA occlusion. This protection was unchanged in BC mice after introgression of the B6 allele of Dce1, the major genetic determinant of variation in pial collaterals among mouse strains. Consistent with this, collateral extent in these and other strains did not differ with sex. Extent of PComAs and primary cerebral arteries also did not vary with sex. No dimorphism was evident for loss of pial collateral number and/or diameter (collateral rarefaction) caused by aging, obesity, and hypertension, nor for collateral remodeling after pMCAO. However, rarefaction was greater in females with long-standing hypertension. We conclude that smaller infarct volume in female mice is not due to greater collateral extent, greater remodeling, or less rarefaction caused by aging, obesity, or hypertension.

SUBMITTER: Faber JE

PROVIDER: S-EPMC5429998 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Sex Differences in the Cerebral Collateral Circulation.

Faber James E JE Moore Scott M SM Lucitti Jennifer L JL Aghajanian Amir A Zhang Hua H

Translational stroke research 20161114 3

Premenopausal women and intact female rodents sustain smaller cerebral infarctions than males. Several sex-dependent differences have been identified as potential contributors, but many questions remain unanswered. Mice exhibit wide variation in native collateral number and diameter (collateral extent) that is dependent on differences in genetic background, aging, and other comorbidities and that contributes to their also-wide differences in infarct volume. Likewise, variation in infarct volume ...[more]

PMID: 27844273

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Project description:Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors.

Project description:Background: The contribution of metabolic profile to the cerebral collateral circulation in acute ischemic stroke (AIS) has not been fully outlined. In this study, we conducted a metabolomic study to assess the relationship between the metabolic biomarkers and the collateral status of AIS. Methods: A two-stage study was conducted from September 2019 to June 2021 in our hospital. There were 96 subjects including 66 patients with AIS and 30 healthy controls in the discovery stage and 80 subjects including 53 patients with AIS and 27 healthy controls in the validation stage. Collateral circulation was assessed by the Tan score based on computed tomographic angiography (CTA). Liquid chromatography-tandem mass spectrometry was used to identify differential metabolic markers. Then, an ELISA was employed to detect the plasma levels of sphingosine-1-phosphate (S1P). Results:There were 114 differential metabolites between patients with AIS and control groups and 37 differential metabolites between good collateral circulation (GCC) and poor collateral circulation (PCC) groups. The pathway enrichment analysis revealed that arginine biosynthesis was the only statistically significant pathway between AIS and control groups and sphingolipid metabolism was the only statistically significant pathway between GCC and PCC groups. The differential metabolites sphinganine-1-phosphate (SA1P) and S1P belong to the sphingolipid metabolism. In the discovery stage, when the GCC group was compared with the PCC group, the receiver operating characteristic (ROC) analysis showed that plasma SA1P relative levels demonstrated an area under the curve (AUC) of 0.719 (95% CI: 0.582-0.834), and S1P levels demonstrated an AUC of 0.701 (95% CI: 0.567-0.819). In addition, both plasma SA1P and S1P relative levels showed significant negative correlations with the 90-day modified Rankin Scale (mRS) score. In the validation sample, higher plasma S1P levels were independent predictors of GCC (p = 0.014), and plasma S1P levels demonstrated an AUC of 0.738 (95% CI: 0.599-0.849) to differentiate patients with GCC from patients with PCC. In addition, plasma S1P levels also showed significant negative correlations with the 90-day mRS score. Conclusion: We first illustrated the association between plasma metabolic profiles and cerebral collateral circulation in patients with AIS. Plasma S1P levels might be a potential diagnostic biomarker for predicting collateral circulation status in patients with AIS.

Dataset Information

Sex Differences in the Cerebral Collateral Circulation.

Publications

Sex Differences in the Cerebral Collateral Circulation.

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