Vasculopathy and Functional Remodeling of the Arterial System Following Compressive Spinal Cord Injury

Severe traumatic spinal cord injury (SCI) not only results in permanent disability, but also severe cardiovascular dysfunction. The development of neurogenic shock which leads to hypotension during the acute stage of SCI further impedes the cord perfusion and thus aggravates the secondary injury. Sustained SCI with the occurrence of autonomic dysreflexia (AD) and intractable hypertension is the leading cause of death in these patients. However, the mechanics and molecular modulation in the arterial system following SCI remain unclear. Our recently published results showed that compensatory increased expression of α1-adrenergic receptors in the medial layers of peripheral arteries, enhancing the responsiveness of α1-adrenergic to stimulation during acute stage of SCI. Although this is the first evidence suggestive of vascular remodeling after traumatic SCI, there are questions remain and not answered. It is not clear whether the vascular endothelium involves in the vasoreactivity change. Vascular endothelium plays a key role in the local regulation of vascular tone and vascular architecture. Endothelial nitric oxide (NO) synthase (eNOS) is the key molecule in respond to the changes of shear stress or blood flow. The decreased production of NO results in vasculopathy had been reported in cardiovascular diseases. In addition, there are limited direct evidences to delineate vascular remodeling. Physiological vascular remodeling occurs in response to changes in blood flow. The changes in lumen diameter are secondary to the structural changes triggered by precise regulation of apoptosis versus proliferation, metalloproteinase activation, coordinated cell migration and organization to change lumen diameter. Taken together, the hemodynamic instability after SCI provides the foundations to ask whether the endothelial dysfunction is the cause of vasculopathy in denervated vessels. This study aims to delineate the pathophysiology of vasculopathy and functional remodeling of the arterial system in traumatic SCI. We hypothesize that 1) decreased intraluminal flow in the denervated vessel results in endothelial dysfunction, which impedes subsequent NO production; 2) decreased NO production further triggers the vascular remodeling in the vessels below the level of SCI, while the vessels above the level of SCI remain intact. The disproportional vascular remodeling causes the AD. To test our hypothesis, the following specific aims are constructed. In the specific aim 1, we will examine the endothelia function in the peripheral arteries after T9 SCI in the acute and chronic stages (postoperative days (POD) 3, 7, 14, 28). Regional blood flow and vasoreactivity in the femoral artery (innervated below T9 levels), superior mesenteric artery (innervated by T4-10 levels), carotid artery (innervated higher than T2 levels) will be measured by an ultrasonic probe and isometric tension experiments (endothelium-dependent and –independent relaxations), respectively. Vascular segments will be analyzed for protein expression and immunohistochemistry for endothelial markers (NO, eNOS). In the specific aim 2, we will investigate the vascular remodeling in the dernervated vessels (below the injury level) and normal vessels (above the injury level) by analyzing the expression of metalloproteinase, α1-adrenergic receptors, and Verhoff staining. The results of this proposal would provide detail pathogenesis of vascular instability after SCI, which may help to design new therapeutic strategies.