Rigid and remodelled: cerebrovascular structure and function after experimental high‐thoracic spinal cord transection

Phillips, Aaron A.; Matin, Nusrat; Frias, B.; Zheng, Mei; Jia, Minghao; West, Christopher R.; Dorrance, Anne M.; Laher, Ismail; Krassioukov, Andrei V.

doi:10.1113/jp270925

Cited by 29 publications

(30 citation statements)

References 63 publications

(66 reference statements)

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“…19,21 The MCA is a critical pathway supplying oxygen and nutrition to the brain, and damage to a functional MCA would lead to central nervous diseases. 22 Because vascular wall thickness and diameters could be altered in vascular diseases, 23 we measured them in offspring. Wall thickness and diameter of the MCA did not show significant differences between the 2 groups.…”

Section: Discussion and Summarymentioning

confidence: 99%

Prenatal Hypoxia Induced Dysfunction in Cerebral Arteries of Offspring Rats

Tang

Chen

et al. 2017

JAHA

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BackgroundHypoxia during pregnancy could cause abnormal development and lead to increased risks of vascular diseases in adults. This study determined angiotensin II (AII)‐mediated vascular dysfunction in offspring middle cerebral arteries (MCA).Methods and ResultsPregnant rats were subjected to hypoxia. Vascular tension in offspring MCA by AII with or without inhibitors, calcium channel activities, and endoplasmic reticulum calcium stores were tested. Whole‐cell patch clamping was used to investigate voltage‐dependent calcium channel currents. mRNA expression was tested using quantitative real‐time polymerase chain reaction. AII‐mediated MCA constriction was greater in male offspring exposed to prenatal hypoxia. AT1 and AT2 receptors were involved in the altered AII‐mediated vasoconstriction. Prenatal hypoxia increased baseline activities of L‐type calcium channel currents in MCA smooth muscle cells. However, calcium currents stimulated by AII were not significantly changed, whereas nifedipine inhibited AII‐mediated vasoconstrictions in the MCA. Activities of IP 3/ryanodine receptor–operated calcium channels, endoplasmic reticulum calcium stores, and sarcoendoplasmic reticulum membrane Ca2+‐ATPase were increased. Prenatal hypoxia also caused dysfunction of vasodilatation via the endothelium NO synthase. The mRNA expressions of AT1A, AT1B, AT2R, Cav1.2α1C, Cav3.2α1H, and ryanodine receptor RyR2 were increased in the prenatal‐hypoxia group.ConclusionsHypoxia in pregnancy could induce dysfunction in both contraction and dilation in the offspring MCA. AII‐increased constriction in the prenatal‐hypoxia group was not mainly dependent on the L‐type and T‐type calcium channels; it might predominantly rely on the AII receptors, IP 3/ryanodine receptors, and the endoplasmic reticulum calcium store as well as calcium ATPase.

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Section: Discussion and Summarymentioning

confidence: 99%

Prenatal Hypoxia Induced Dysfunction in Cerebral Arteries of Offspring Rats

Tang

Chen

et al. 2017

JAHA

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“…Surgery and animal care were conducted according to standard procedures in our laboratory to perform a complete spinal transection at the T3 spinal segment. 25 Four male rats (age = nine weeks, mass = 250-350 g; Harlan Laboratories, Indianapolis, IN) were used initially to develop the translational model of transient hypertension and ensuing cerebral hyperperfusion. Next, using this model, 50 male rats (identical age, strain, and supplier) were randomly assigned either ( Fig.…”

Section: Pre-clinical Modelmentioning

confidence: 99%

Transient Hypertension after Spinal Cord Injury Leads to Cerebrovascular Endothelial Dysfunction and Fibrosis

Phillips

Matin

Jia

et al. 2018

Journal of Neurotrauma

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We aimed to create a clinically relevant pre-clinical model of transient hypertension, and then evaluate the pathophysiological cerebrovascular processes resulting from this novel stimulus, which has recently been epidemiologically linked to cerebrovascular disease. We first developed a clinically relevant model of transient hypertension, secondary to induced autonomic dysreflexia after spinal cord injury and demonstrated that in both patients and rats, this stimulus leads to drastic acute cerebral hyperperfusion. For this, iatrogenic urodynamic filling/penile vibrostimulation was completed while measuring beat-by-beat blood pressure and cerebral blood flow (CBF) in patients. We then developed a rodent model mimicking the clinical reality by performing colorectal distention (to induce autonomic dysreflexia) using pre-clinical beat-by-beat blood pressure and CBF assessments. We then performed colorectal distension in rats for four weeks (6x/day) to evaluate the long-term cerebrovascular consequences of transient hypertension. Outcome measures included middle cerebral artery endothelial function, remodeling, profibrosis and perivascular innervation; measured via pressure myography, immunohistochemistry, molecular biology, and magnetic resonance imaging. Our model demonstrates that chronic repetitive cerebral hyperperfusion secondary to transient hypertension because of autonomic dysreflexia: (1) impairs cerebrovascular endothelial function; (2) leads to profibrotic cerebrovascular stiffening characterized by reduced distensibility and increased collagen deposition; and (3) reduces perivascular sympathetic cerebrovascular innervation. These changes did not occur concurrent to hallmark cerebrovascular changes from chronic steady-state hypertension, such as hypertrophic inward remodeling, or reduced CBF. Chronic exposure to repetitive transient hypertension after spinal cord injury leads to diverse cerebrovascular impairment that appears to be unique pathophysiology compared with steady-state hypertension in non-spinal cord injured models.

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“…For instance, spinal cord injury patients suffer frequently from dramatic BP instability (e.g. orthostatic hypotension (OH)) which leads to cardiac and cerebral complications (Phillips et al 2016). Better understanding of the PVN-RVLM excitatory glutamatergic interneuronal circuitry and communication relays may reveal new potential therapies.…”

Section: Future Directions and Clinical Implicationsmentioning

confidence: 99%