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

Abstract

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.

Six weeks of high‐intensity interval training to exhaustion attenuates dynamic cerebral autoregulation without influencing resting cerebral blood velocity in young fit men

“…Further research is required to elucidate whether a threshold exists above which CRF will be associated with an attenuated dCA. In addition, Phillips et al () have recently reported that 4 weeks of repeated transient hypertension induced by colorectal distension in rats after spinal cord injury lead to impairments of the brain vasculature such as cerebrovascular endothelial dysfunction and profibrotic cerebrovascular stiffness (Phillips et al, ). Unfortunately, we did not monitor BP changes during our HIIT sessions.…”

Implications of habitual endurance and resistance exercise for dynamic cerebral autoregulation

“…Regular exposure to such extreme intermittent hypertension, and associated rapid changes in cerebral perfusion, may induce structural modifications in the cerebrovasculature. For example, pre‐clinical animal models utilizing 4 weeks of repeated transient hypertension induced cerebrovascular endothelial dysfunction and profibrotic mediated cerebrovascular stiffness (Phillips et al., ). We speculate that this modification may underlie the tendency for a reduced phase in the resistance‐trained group.…”

Diverse cognitive impairment after spinal cord injury is associated with orthostatic hypotension symptom burden

“…We have reported as many as 41 autonomic dysreflexia events occur each day (mean = 11/day) in individuals with high-level SCI [28]. Recent evidence in pre-clinical models demonstrates diverse cerebrovascular impairments with chronic exposure to repetitive episodes of transient hypertension following SCI [29]. Chronic hypertension in non-disabled individuals is strongly and consistently associated with cognitive decline [30].…”