Transplanting neural progenitor cells improves neural regulation but not hormonal reliance of cardiovascular function following spinal cord injury

High-level spinal cord injury (SCI) often reduces neural regulation of cardiovascular function. During the chronic phase, humoral regulation via the renin-angiotensin system (RAS) is enhanced to compensatorily maintaining blood pressure. It was recently shown that transplanting early-stage neurons into the injured cord mitigates cardiovascular disorders. However, the mechanisms underlying this recovery remain largely unknown. Here, we employed various pharmacological interventions to elucidate whether this strategic transplantation affects the imbalance of neuroendocrine regulation of hemodynamics and the role of specific serotonergic and catecholaminergic components. Female rats received a complete crush at the 4 th thoracic spinal cord. Embryonic neural progenitor cells harvested from the raphe nuclei (RN-NPCs) or the spinal cord (SC-NPCs) were transplanted into the lesion. Naïve rats or injury alone served as controls. After 8-9 weeks, radio-telemetric recordings demonstrated that both implants decreased tachycardia at rest and diminished the frequency or severity of autonomic dysreflexia. Pharmacological interventions demonstrated that both NPC grafts partially restored neural regulation of blood pressure without normalizing the aberrant RAS hyperactivity. Subsequently, specific neural mechanisms were explored through intrathecal administration of the 5-HT 2A antagonist ketanserin, the 5-HT 1A antagonist WAY100635, or the α1-adrenoreceptor antagonist prazosin. It revealed that graft-derived serotonergic signaling was involved in the restoration of resting heart rate via 5-HT 2A receptors but did not attenuate autonomic dysreflexia. In addition, catecholaminergic mechanisms remained critical for blood pressure maintenance after SCI. Ultimately, the results provide insight into understanding the mechanistic nuances associated with cell therapy for SCI-induced cardiovascular dysfunction. Significance Statement High-level spinal cord injury (SCI) often impairs neural regulation of cardiovascular function, inducing compensatory hyperactivation of the renin-angiotensin system (RAS) to maintain blood pressure. Transplanting embryonic neural progenitor cells (NPCs), harvested from the fetal raphe nuclei or spinal cord, partially restored neural control of the vasculature but did not ameliorate high RAS reliance. Graft-derived serotonin transmission was involved in the restoration of hemodynamics via 5-HT 2A receptors but not dysreflexic responses. Meanwhile, catecholaminergic mechanisms continued to mediate blood pressure regulation after SCI. The results provide new insight to better understand the mechanistic nuances associated with cell therapy for SCI-induced cardiovascular dysfunction.