Ultrafast Doppler imaging and Ultrasound Localization Microscopy reveal the complexity of vascular rearrangement in chronic spinal lesion

Abstract Acute spinal cord injury (SCI) leads to severe damage to the microvascular network. The process of spontaneous repair is accompanied by formation of new blood vessels; their functionality, however, presumably very important for functional recovery, has never been clearly established, as most studies so far used fixed tissues. Here, combining ultrafast Doppler imaging and Ultrasound Localization Microscopy (ULM) on the same animals, we proceeded at a detailed analysis of structural and functional vascular alterations associated with the establishment of chronic SCI, both at macroscopic and microscopic scales. Using a standardized animal model of SCI, our results demonstrate striking hemodynamic alterations in several subparts of the spinal cord: a reduced blood velocity in the lesion site, and an asymmetrical hypoperfusion caudal but not rostral to the lesion. In addition, the worsening of many evaluated parameters at later time points suggests that the neoformed vascular network is not yet fully operational, and reveals ULM as an efficient in vivo readout for spinal cord vascular alterations. Finally, we show statistical correlations between the diverse biomarkers of vascular dysfunction and SCI severity. The imaging modality developed here will allow evaluating recovery of vascular function over time in pre-clinical models of SCI. Also, used on SCI patients in combination with other quantitative markers of neural tissue damage, it may help classifying lesion severity and predict possible treatment outcomes in patients.

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Intraoperative Ultrasound Localization Microscopy of Human Spinal Cord: An In Vivo Feasibility Study

2020 IEEE International Ultrasonics Symposium (IUS) ◽

10.1109/ius46767.2020.9251839 ◽

2020 ◽

Author(s):

Yayu Hao ◽

Linkai Jing ◽

Qiong He ◽

Guihuai Wang ◽

Jianwen Luo

Keyword(s):

Spinal Cord ◽

Feasibility Study ◽

Intraoperative Ultrasound ◽

Localization Microscopy ◽

Human Spinal Cord ◽

Ultrasound Localization

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Use of the PV[O]H algorithm as a noninvasive imaging modality for spinal cord injury in vivo in a rat model

Biophotonics Congress: Optics in the Life Sciences Congress 2019 (BODA,BRAIN,NTM,OMA,OMP) ◽

10.1364/boda.2019.jt4a.39 ◽

2019 ◽

Author(s):

Seth Fillioe ◽

Kyle Kelly Bishop ◽

Alexander Vincent Struck Jannini ◽

Jon Kim ◽

Ricky McDonough ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Imaging Modality ◽

Noninvasive Imaging ◽

Cord Injury ◽

Noninvasive Imaging Modality

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Acute heat stress reduces biomarkers of endothelial activation but not macro- or microvascular dysfunction in cervical spinal cord injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00693.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. H722-H733 ◽

Cited By ~ 6

Author(s):

Geoff B. Coombs ◽

Otto F. Barak ◽

Aaron A. Phillips ◽

Tanja Mijacika ◽

Zoe K. Sarafis ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Femoral Artery ◽

Vascular Function ◽

Vascular Dysfunction ◽

Water Immersion ◽

Reactive Hyperemia ◽

Endothelial Activation ◽

Hot Water ◽

Cord Injury

Cardiovascular diseases (CVD) are highly prevalent in spinal cord injury (SCI), and peripheral vascular dysfunction might be a contributing factor. Recent evidence demonstrates that exposure to heat stress can improve vascular function and reduce the risk of CVD in uninjured populations. We therefore aimed to examine the extent of vascular dysfunction in SCI and the acute effects of passive heating. Fifteen participants with cervical SCI and 15 uninjured control (CON) participants underwent ultrasound assessments of vascular function and venous blood sampling for biomarkers of endothelial activation (i.e., CD62e+) and apoptosis (i.e., CD31+/42b−) before and after a 60-min exposure to lower limb hot water immersion (40°C). In SCI, macrovascular endothelial function was reduced in the brachial artery [SCI: 4.8 (3.2)% vs. CON: 7.6 (3.4)%, P = 0.04] but not the femoral artery [SCI: 3.7 (2.6)% vs. CON: 4.0 (2.1)%, P = 0.70]. Microvascular function, via reactive hyperemia, was ~40% lower in SCI versus CON in both the femoral and brachial arteries ( P < 0.01). Circulating concentrations of CD62e+ were elevated in SCI versus CON [SCI: 152 (106) microparticles/µl vs. CON: 58 (24) microparticles/µl, P < 0.05]. In response to heating, macrovascular and microvascular function remained unchanged, whereas increases (+83%) and decreases (−93%) in antegrade and retrograde shear rates, respectively, were associated with heat-induced reductions of CD62e+ concentrations in SCI to levels similar to CON ( P = 0.05). These data highlight the potential of acute heating to provide a safe and practical strategy to improve vascular function in SCI. The chronic effects of controlled heating warrant long-term testing. NEW & NOTEWORTHY Individuals with cervical level spinal cord injury exhibit selectively lower flow-mediated dilation in the brachial but not femoral artery, whereas peak reactive hyperemia was lower in both arteries compared with uninjured controls. After 60 min of lower limb hot water immersion, femoral artery blood flow and shear patterns were acutely improved in both groups. Elevated biomarkers of endothelial activation in the spinal cord injury group decreased with heating, but these biomarkers remained unchanged in controls.

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Spinal cord injury and vascular function: Evidence from diameter matched vessels

Journal of Applied Physiology ◽

10.1152/japplphysiol.00329.2020 ◽

2020 ◽

Author(s):

Massimo Venturelli ◽

Markus Amann ◽

Joel D. Trinity ◽

Stephen J. Ives ◽

Russell S. Richardson

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Shear Rate ◽

Vascular Function ◽

Vascular Dysfunction ◽

Reactive Hyperemia ◽

Cord Injury ◽

Vascular Responsiveness ◽

Functional Limb ◽

Flow Mediated Vasodilation

The effect of a spinal cord injury (SCI) on vascular function has been clouded by both the physiological and mathematical bias of assessing vasodilation in arteries with differing diameters both above and below the lesion and when comparing with healthy, non-disabled controls (CTRL). Thus, we measured vascular function, with flow mediated vasodilation (FMD), in 10 SCI and 10 CTRL with all arteries matched for diameter (≈0.5cm): brachial (BA, arm, functional-limb in both groups) and popliteal artery (PA, leg, disused-limb in SCI, functional-limb in CTRL). PA %FMD was significantly attenuated in SCI (5.6±0.6%) compared to CTRL (8.4±1.3%), with no difference in the BA (SCI: 8.6±0.9%; CTRL: 8.7±0.7%). However, unlike the arm, where muscle mass was preserved, the legs of the SCI were significantly smaller than CTRL (~70%). Thus, reactive hyperemia (RH), which is heavily dependent upon the volume of muscle occluded, in the PA was attenuated in the SCI (144±22ml) compared to CTRL (258±16ml), but not different in the BA. Consequently, shear rate was significantly diminished in the PA of the SCI, such that %FMD/shear rate (vascular responsiveness) was actually greater in the SCI (1.5±0.1%・s-1) than CTRL (1.2±0.1%・s-1). Of note, this was significantly greater than both their own BA (0.9±0.1%・s-1) and that of the CTRL (0.9±0.1%・s-1). Therefore, examining vessels of similar size, this study reveals normal vascular function above the lesion and vascular dysfunction below the lesion. However, below the lesion there was, actually, evidence of increased vascular responsiveness in this population.

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Faculty Opinions recommendation of Effect of vascular endothelial growth factor treatment in experimental traumatic spinal cord injury: in vivo longitudinal assessment.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.9908956.11172056 ◽

2011 ◽

Author(s):

Jose V Lafuente ◽

Enrike Argandoña

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Vascular Endothelial Growth Factor ◽

Traumatic Spinal Cord Injury ◽

Vascular Endothelial ◽

Longitudinal Assessment ◽

Cord Injury ◽

Endothelial Growth Factor ◽

Growth Factor Treatment

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Further studies on free-radical pathology in the major central nervous system disorders: effect of very high doses of methylprednisolone on the functional outcome, morphology, and chemistry of experimental spinal cord impact injury

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y82-210 ◽

1982 ◽

Vol 60 (11) ◽

pp. 1415-1424 ◽

Cited By ~ 150

Author(s):

H. B. Demopoulos ◽

E. S. Flamm ◽

M. L. Seligman ◽

D. D. Pietronigro ◽

J. Tomasula ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Free Radical ◽

Tissue Injury ◽

Functional Restoration ◽

Radical Reactions ◽

Free Radical Reactions ◽

Cord Injury

The hypothesis that pathologic free-radical reactions are initiated and catalyzed in the major central nervous system (CNS) disorders has been further supported by the current acute spinal cord injury work that has demonstrated the appearance of specific, cholesterol free-radical oxidation products. The significance of these products is suggested by the fact that: (i) they increase with time after injury; (ii) their production is curtailed with a steroidal antioxidant; (iii) high antioxidant doses of the steroidal antioxidant which curtail the development of free-radical product prevent tissue degeneration and permit functional restoration. The role of pathologic free-radical reactions is also inferred from the loss of ascorbic acid, a principal CNS antioxidant, and of extractable cholesterol. These losses are also prevented by the steroidal antioxidant. This model system is among others in the CNS which offer distinctive opportunities to study, in vivo, the onset and progression of membrane damaging free-radical reactions within well-defined parameters of time, extent of tissue injury, correlation with changes in membrane enzymes, and correlation with readily measurable in vivo functions.

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A Collagen-Based Scaffold for Promoting Neural Plasticity in a Rat Model of Spinal Cord Injury

Polymers ◽

10.3390/polym12102245 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2245

Author(s):

Jue-Zong Yeh ◽

Ding-Han Wang ◽

Juin-Hong Cherng ◽

Yi-Wen Wang ◽

Gang-Yi Fan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Neural Plasticity ◽

Collagen Scaffold ◽

Glial Scar ◽

Beneficial Effects ◽

Cord Injury

In spinal cord injury (SCI) therapy, glial scarring formed by activated astrocytes is a primary problem that needs to be solved to enhance axonal regeneration. In this study, we developed and used a collagen scaffold for glial scar replacement to create an appropriate environment in an SCI rat model and determined whether neural plasticity can be manipulated using this approach. We used four experimental groups, as follows: SCI-collagen scaffold, SCI control, normal spinal cord-collagen scaffold, and normal control. The collagen scaffold showed excellent in vitro and in vivo biocompatibility. Immunofluorescence staining revealed increased expression of neurofilament and fibronectin and reduced expression of glial fibrillary acidic protein and anti-chondroitin sulfate in the collagen scaffold-treated SCI rats at 1 and 4 weeks post-implantation compared with that in untreated SCI control. This indicates that the collagen scaffold implantation promoted neuronal survival and axonal growth within the injured site and prevented glial scar formation by controlling astrocyte production for their normal functioning. Our study highlights the feasibility of using the collagen scaffold in SCI repair. The collagen scaffold was found to exert beneficial effects on neuronal activity and may help in manipulating synaptic plasticity, implying its great potential for clinical application in SCI.

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