The Role of Endothelial Dysfunction in Peripheral Blood Nerve Barrier: Molecular Mechanisms and Pathophysiological Implications

Abstract

The exchange of solutes between the blood and the nerve tissue is mediated by specific and high selective barriers in order to ensure the integrity of the different compartments of the nervous system. At peripheral level, this function is maintained by the Blood Nerve Barrier (BNB) that, in the presence, of specific stressor stimuli can be damaged causing the onset of neurodegenerative processes. An essential component of BNB is represented by the endothelial cells surrounding the sub-structures of peripheral nerves and increasing evidence suggests that endothelial dysfunction can be considered a leading cause of the nerve degeneration. The purpose of this review is to highlight the main mechanisms involved in the impairment of endothelial cells in specific diseases associated with peripheral nerve damage, such as diabetic neuropathy, erectile dysfunction and inflammation of the sciatic nerve.

Keywords: Blood Nerve Barrier (BNB); diabetic neuropathy; endothelial dysfunction; erectile dysfunction; neuropathic pain; nitric oxide; nitric oxide synthase (NOS); peripheral nerve injury.

Figure 1

Nitric oxide synthase (NOS) regulation. Schematic representation of the phosphorylation sites on the endothelial isoform (eNOS) enzyme and of the mechanical and humoral factors involved. Shear stress and HDL increase the phosphorylation on eNOS-Ser¹¹⁴ site; the eNOS agonistic VEGF, statins, and bradykinin increase the phosphorylation of eNOS-Ser⁶¹⁵. Moreover, the phosphorylation of eNOS-Ser¹¹⁷⁷ and eNOS-Ser⁶³³ leads to an increase of eNOS activity, on the other hand the phosphorylation of eNOS-Thr⁴⁹⁵ leads to a reduction of the activity of this enzyme.

Figure 2

NOS activity. Under normal condition calcium is associates with calmodulin to activate the enzyme eNOS which produces NO from its precursor l-arginine forming l-citrulline. In this context the enzymatic reaction generating NO involves the transfer of electrons from NADPH, via the flavins to the heme and consequently the substrate l-arginine is oxidized to l-citrulline and NO. To efficiently produce NO, eNOS must effectively coordinate the binding of multiple substrates and cofactors such as Tetrahydrobiopetrin (BH4). Disruption of this highly coordinated catalysis (uncoupled eNOS) can result in the production of superoxide and peroxynitrite. Other sources of ROOS are mitochondria, phospholipase A2, Cyclooxygenase, Cyt P450, xanthine oxidase, NADPH oxidase.

Figure 3

ER stress. The increased ROS levels or insulin resistance lead to ER stress in endothelial cells. While insulin resistance altered the production of NO, the reduced bioavailability of NO induces an increase of oxidative stress leading to an impaired calcium homeostasis and to the activation of proapoptotic signals such as JNK/p38 or caspase-12 promoting apoptosis. IRE-1 through the apoptotic signal ASK1 stimulates proapoptotic signals. Moreover, ASK1 decrease eNOS levels and causes NO deficiency.

Figure 4

Dysfunction of endothelium. The injury of endothelial cells is accompanied by neuroinflammation due to increased expression of pro-inflammatory factors.

Figure 5

Endothelium dysfunction and leukocytes infiltration. During pathological conditions, such as inflammation, infection, and injury of peripheral nerve, an alteration of endothelial intercellular junction proteins occurs. A reduction of tight junction proteins, such as claudins and occludins, determines a leukocytes infiltration.