ABSTRACT
Children with orthostatic intolerance (OI) have exaggerated decreases in heart rate variability (HRV) and suppression of baroreflex sensitivity (BRS) with standing. Accompanying brain transmitter and metabolite profiles are unknown. In this study, we used proton (1H) magnetic resonance spectroscopy (1H-MRS) to quantify markers of neuronal and glial integrity in a pilot study of children with OI compared with asymptomatic controls. Eighteen participants ages 10-18 yr were evaluated for blood pressure, heart rate (HR), and calculated indexes of autonomic function in supine and upright positions and, within an average of 2 wk, underwent 1H-MRS scans of dorsal medulla on a clinical 3T magnet while supine. As a result, of the 18 participants, 11 tested positive for OI and 7 did not. OI subjects exhibited higher HR and lower HRV and high-frequency α-index (HFα), an index of parasympathetic vagal tone, during standing compared with non-OI. HRV, sequence all (Seq All), high- and low-frequency (HFα and LFα) estimates of the spontaneous BRS decreased significantly, while BP variabilty increased significantly during standing only in subjects with OI. OI subjects had higher myoinositol (mIns) and total choline (tCho), markers of glial inflammation. Upright HFα and Seq All inversely correlated to supine tCho and mIns, respectively, independent of age and sex. In conclusions, in this pilot study, children with OI exhibit higher mIns and tCho in the dorsal medulla while supine that may reflect the well-established impairment in regulation of the autonomic nervous system upon standing. Neuroinflammation as an underlying cause or consequence of autonomic dysfunction is an intriguing possibility requiring further study.NEW & NOTEWORTHY (1H) magnetic resonance spectroscopy detected elevated markers of neuroinflammation in the dorsal medulla in children with impaired autonomic responses to head upright tilt. This first report of altered brain metabolites in this population provides a basis for future clinical studies using this methodology to aide in understanding complex autonomic disease states.
Subject(s)
Autonomic Nervous System/physiopathology , Baroreflex , Choline/metabolism , Inflammation Mediators/metabolism , Inositol/metabolism , Medulla Oblongata/metabolism , Orthostatic Intolerance/metabolism , Adolescent , Age Factors , Blood Pressure , Case-Control Studies , Child , Female , Heart Rate , Humans , Male , Orthostatic Intolerance/diagnosis , Orthostatic Intolerance/physiopathology , Patient Positioning , Pilot Projects , Proton Magnetic Resonance Spectroscopy , Supine Position , Up-RegulationABSTRACT
The glycocalyx is a key mechanosensor on the surfaces of vascular cells (endothelial cells and smooth muscle cells), and recently, we reported that the redistribution of the hemodynamic factors in tail-suspended (TS) hindlimb-unloaded rats induces the dimensional adaptation of the endothelial glycocalyx in a regional-dependent manner. In the present study, we investigated the coverage and gene expression of the glycocalyx and its possible relationship with smooth muscle contractility in the conduit arteries from the TS rats. The coverage of the glycocalyx, determined by the area analysis of the fluorescein isothiocyanate-labeled wheat germ agglutinin (WGA-FITC) staining to the cryosections of rat vessels, showed a 27.2% increase in the common carotid artery, a 13.3 and 8.0% decrease in the corresponding abdominal aorta and the femoral artery after 3 wk of tail suspension. The relative mRNA levels of syndecan-2, 3, 4, glypican-1, smooth muscle protein 22 (SM22), smoothelin (SMTN), and calponin were enhanced to 1.40, 1.53, 1.70, 1.90, 2.93, 2.30, and 5.23-fold, respectively, in the common carotid artery of the TS rat. However, both glycocalyx-related genes and smooth muscle contractile apparatus were totally or partially downregulated in the abdominal aorta and femoral artery of the TS rat. A linear positive correlation between the normalized coverage of glycocalyx and normalized mRNA levels of SM22, SMTN, and calponin exists. These results suggest the regional-dependent adaptation of the glycocalyx in simulated microgravity condition, which may affect its mechanotransduction of shear stress to regulate the contractility of the smooth muscle, finally contributing to postspaceflight orthostatic intolerance.
Subject(s)
Carotid Artery, Common/physiology , Femoral Artery/physiology , Glycocalyx/physiology , Hindlimb Suspension/physiology , Muscle Contraction/physiology , Myocytes, Smooth Muscle/physiology , Vasoconstriction/physiology , Adaptation, Physiological/physiology , Animals , Aorta, Abdominal/metabolism , Aorta, Abdominal/physiology , Carotid Artery, Common/metabolism , Endothelial Cells/metabolism , Endothelial Cells/physiology , Female , Femoral Artery/metabolism , Glycocalyx/metabolism , Male , Mechanotransduction, Cellular/physiology , Muscle Proteins/metabolism , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/physiology , Myocytes, Smooth Muscle/metabolism , Orthostatic Intolerance/metabolism , Orthostatic Intolerance/physiopathology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Stress, Mechanical , Weightlessness Simulation/methodsABSTRACT
Previous animal studies by using tail-suspended hindlimb-unloaded rat model have shown that simulated microgravity-induced vessel structural and functional remodeling may be anatomic region dependent. However, little care has been taken to assess the structural adaptation of the endothelial glycocalyx, the apical surface of the endothelium, the key mechanosensor mediating nitric oxide (NO) production, and the natural protective barrier of the vasculature. Therefore, the present study extended simulated microgravity-induced vessel remodeling to the endothelial glycocalyx level. The percents of bone mineral density (BMD) change from both control and tail-suspended (TS) rats were measured by micro-computed tomography (Micro-CT). Structural parameters such as the luminal diameter (D), the thickness of each layer, the ratio of intima to media (IMR), the cross-sectional areas of the intima (CSAI) and media (CSAM) of vessels from three different regions (the common carotid artery, abdominal aorta, and femoral artery) were assessed by hematoxylin and eosin staining. Dimensions of the glycocalyx above, below, and away from the endothelial cell nucleus were examined by fluorescein isothiocyanate-labeled wheat germ agglutinin (WGA-FITC) binding to the cryosection of vessels. Our results show that 3-week tail suspension of rats increases the thickness and CSA of the abdominal aortic endothelium by 23.7 and 21.1%, respectively, thickens the media layer of the common carotid artery by 34.0%, and increases the luminal diameter, the CSA of the intima and media of the femoral artery by 75.7, 93, and 61.2%, respectively. Correspondingly, the dimension of the glycocalyx away from the common carotid arterial and the abdominal aortic endothelial cell nucleus from tail-suspended rats shows a 1.66- and 1.64-fold increase respectively, while it shows a 0.79-fold reduction on the top of the femoral endothelial cells. These results suggest that simulated microgravity induces vascular endothelial glycocalyx remodeling in a regional-dependent manner. The perturbation of the endothelial glycocalyx at the lower body artery may be the first event of vascular remodeling initiating endothelial dysfunction, contributing to postspaceflight orthostatic intolerance.
