Autonomic Dysreflexia in Spinal Cord Injury: Mechanisms and Prospective Therapeutic Targets

Abstract

High-level spinal cord injury (SCI) often results in cardiovascular dysfunction, especially the development of autonomic dysreflexia. This disorder, characterized as an episode of hypertension accompanied by bradycardia in response to visceral or somatic stimuli, causes substantial discomfort and potentially life-threatening symptoms. The neural mechanisms underlying this dysautonomia include a loss of supraspinal control to spinal sympathetic neurons, maladaptive plasticity of sensory inputs and propriospinal interneurons, and excessive discharge of sympathetic preganglionic neurons. While neural control of cardiovascular function is largely disrupted after SCI, the renin-angiotensin system (RAS), which mediates blood pressure through hormonal mechanisms, is up-regulated after injury. Whether the RAS engages in autonomic dysreflexia, however, is still controversial. Regarding therapeutics, transplantation of embryonic presympathetic neurons, collected from the brainstem or more specific raphe regions, into the injured spinal cord may reestablish supraspinal regulation of sympathetic activity for cardiovascular improvement. This treatment reduces the occurrence of spontaneous autonomic dysreflexia and the severity of artificially triggered dysreflexic responses in rodent SCI models. Though transplanting early-stage neurons improves neural regulation of blood pressure, hormonal regulation remains high and baroreflex dysfunction persists. Therefore, cell transplantation combined with selected RAS inhibition may enhance neuroendocrine homeostasis for cardiovascular recovery after SCI.

Keywords: blood pressure; neural relay; renin-angiotensin system; serotonergic modulation; sympathetic regulation.

Figure 1.

Neural regulation of cardiovascular function. Schematic diagrams illustrate neural circuitry controlling the cardiovascular system. The nucleus tractus solitarius (NTS) receives afferent input of arterial pressure from the baroreceptors located along the aortic arch and carotid sinus. Its output projects to 1) parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) and the nucleus ambiguous (NA) and 2) the caudal ventrolateral medulla (CVLM) in the medulla oblongata. Inhibitory neurons in the CVLM innervate the rostral ventrolateral medulla (RVLM) where presympathetic neurons project down to sympathetic preganglionic neurons in the intermediolateral column (IML) of the thoracolumbar spinal cord to regulate sympathetic activity. Created with Biorender.com.

Figure 2.

An illustration describing the classic hormonal regulation of cardiovascular function. The renin-angiotensin system is involved in mediating basal hemodynamic function, albeit to a lesser extent than the sympathetic arm. In response to low blood pressure, renin is secreted from juxtaglomerular cells in the kidneys and subsequently cleaves the propeptide angiotensinogen to form the inactive peptide angiotensin I. The rate-limiting protein angiotensin-converting enzyme (ACE), produced by the endothelium in blood vessels of the lungs, then cleaves angiotensin I into the active hormone angiotensin II. This hormone induces an increase in blood pressure through vasoconstriction, facilitation of sympathetic activity, aldosterone release, and sodium and water retention from the distal convoluted tubules. Created with Biorender.com.

Figure 3.

Schematic diagrams of the renin-angiotensin system (RAS). The two arms of the RAS have different functions. Components in the RAS include renin, angiotensin-converting enzyme (ACE), ACE2, angiotensin (Ang) I and II and other derivatives, Ang II type 1 receptor (AT₁R), and Mas receptor (MasR). The pressor arm (ACE/Ang II/AT₁R) mediates vasoconstriction to increase blood pressure, whereas the depressor arm (ACE2/Ang-[1-7]/MasR) is counterregulatory to the pressor arm and decreases blood pressure by vasodilatory effects.

Figure 4.

Naturally-occurring or colorectal distension-induced autonomic dysreflexia. (A) An adult rat received a complete T2 spinal cord injury. Eight weeks later, blood pressure and heart rate (HR) were recorded for 24 hours. Spontaneous (naturally occurring) autonomic dysreflexia was detected with a script written in MATLAB software. Representative trace shows a typical spontaneous autonomic dysreflexia event. The vertical lines indicate the start (green) and end (red) of the event. (B) Colorectal distension (CRD)–induced autonomic dysreflexia. Three weeks after a complete T4 spinal transection, CRD was performed to mimic constipation and trigger an episode of autonomic dysreflexia, characterized by hypertension accompanied by bradycardia. MAP, mean arterial pressure.

Figure 5.

Illustration of autonomic regulation of cardiovascular function and intraspinal plasticity after spinal cord injury (SCI). In an intact spinal cord, supraspinal spinal vasomotor pathways (red) derived from the rostral ventrolateral medulla (RVLM) excite sympathetic preganglionic neurons within the thoracic spinal cord. These neurons in turn evoke excitation of postganglionic neurons within the peripheral sympathetic chain to excite effector organs and vasculature. After SCI, supraspinal regulation of sympathetic activity is lost below the lesion. Subsequent aberrant sprouting of pelvic primary afferents (black) and their target propriospinal interneurons (PIs; blue) are involved in the development of dysautonomia. Created with Biorender.com. BP, blood pressure; DRG, dorsal root ganglion; HR, heart rate.

Figure 6.

Transplanting embryonic raphe neural progenitor cells (NPCs) may reconstitute serotonergic regulation of sympathetic function. Ten weeks after grafting E14 raphe nuclei–derived NPCs into the lesion site of a T4-crushed spinal cord, immunostaining shows that (A) the graft integrated into the spinal cord by bridging two stumps in a series of longitudinal sections. (B-D) Many serotonergic neurons (5-HT⁺) expressing NeuN are evident in the graft. (E) Surviving NPCs produce dense serotonergic fibers that project to the caudal intermediolateral column autonomic regions, innervating fluorogold (FG)–labeled SPNs. Scale bars: A, 2 mm; C, 0.2 mm; D, 30 μm; E, 50 μm. GFP, green fluorescent protein; 5-HT, 5-hydroxytryptamine.

Box 1.

The development of autonomic dysreflexia following spinal cord injury (SCI). Created with Biorender.com.

Box 2.

Cell transplantation strategy to restore cardiovascular function. Created with Biorender.com.