Degeneration of the cervical spine can cause biomechanical imbalances in the cervical spine [13] and direct compression of the vertebral basilar artery (VBA) [14]. It can also stimulate the cervical sympathetic nerves leading to inadequate blood supply of VBA [2], and then cause symptoms of vertigo. The anterior cervical decompression and fusion procedure can improve the biomechanical imbalance caused by cervical degeneration and remove the posterior longitudinal ligament (PLL) containing the sympathetic nerves, thus effectively relieving vertigo symptoms [15, 16]. Therefore, vertigo symptoms can be efficiently alleviated by improving biomechanics and suppressing sympathetic nerves.
Massage is an external Chinese medicine treatment method that applies suitable mechanical force to specific parts of the human body, and converts the mechanical force into electrical signals through surface receptors and transmits them to the central nervous system in the form of nerve impulses, ultimately playing a therapeutic role. Back and hand massage can relax subjects and produce sympathetic inhibition in the form of lower heart rate and diastolic blood pressure[17, 18]. Our previous study[7] also confirmed the possible changes in sympathetic excitability during massage to improve vertebral artery blood supply. In related clinical studies[19, 20], massage therapy significantly improved the symptoms of vertigo in patients and was more effective than acupuncture and betahistine. Our results (Fig. 1) suggested that massage treatment improved the blood flow of the vertebral artery, and this improvement becomes more pronounced with time. The pathological results (Fig. 3) showed that the morphology and cellular arrangement of the vertebral artery were also improved in the massage group, and these improvements were superior to those in EA group. This indicated that massage had the advantage in promoting soft tissue recovery compared with EA. The improvement of soft tissue balance was conducive to the reestablishment of cervical spine balance. The restoration of cervical spine balance reduced the compression state of blood vessels and nerves, thus playing a long-term and stable role in increasing blood volume.
NE is a well-known vasoconstrictor, an important neurotransmitter secreted by sympathetic nerves, which can affect some arterial diseases by inhibiting the proliferation of vascular smooth muscle cells (VSMCs) [21, 22]. It has been shown that stimulation of the cervical sympathetic ganglia could increase NE levels and decrease basilar artery (BA) blood supply, whereas adrenergic receptor blockade could inhibit this effect [4]. One study also found in a CSA rabbit model [23] that stimulation of the cervical sympathetic ganglion secretes large amounts of NPY and tyrosine hydroxylase (TH), resulting in spasms and reduced blood supply to the vertebral artery. NPY is a co-transmitter released from the postsympathetic ganglia, especially at higher levels of sympathetic excitation [24]. Elevated sympathetic stress leads to increased NPY and NE release [25]. NPY and NE have a synergistic effect, jointly regulating vascular tone and potentiating NE-mediated vasoconstriction [26]. Therefore, the neurotransmitters NPY and NE secreted by cervical sympathetic nerves are closely related to vertebral artery blood flow. The results indicated that (Fig. 2) that massage treatment significantly decreased the release of two important sympathetic transmitters, NPY and NE, while improving vertebral artery blood flow. This may be due to the massage relaxing the soft tissues of the neck and reducing sympathetic arousal, thereby improving the blood flow of the vertebral artery, which also suggested that there may be a neuro-vascular regulation mechanism in the treatment of CSA.
It has been found [27, 28] that by inhibiting sympathetic excitability, serum NE levels can be reduced and the p38MAPK signaling pathway can be inhibited, causing intracellular reactive oxygen species (ROS) levels are reduced, thereby reducing the degree of endoplasmic reticulum stress (ERS) in the cell. Stellate ganglion blockade could also reduce ERS overactivation in arterial tissue by inhibiting sympathetic excitability, thereby improving vascular calcification [29].The most important protective pathway of ERS is the unfolded protein response (UPR) [30], however, excessive ERS can lead to an imbalance in the regulatory capacity of the UPR and promote CHOP protein activity, which in turn induces apoptosis [31]. The results of the present study demonstrated (Figs. 2, 5) that massage treatment reduced sympathetic neurotransmitter release along with reduced CHOP protein expression in vertebral arteries and cerebella, suggesting that massage can mitigate excessive activation of ERS through the UPR pathway by weakening sympathetic excitability.
Overexactivation of ERS will lead to the onset and development of apoptosis [32, 33]. Many studies in recent years [34–36] have shown that the process of apoptosis was closely related to the treatment of cervical spondylotic myelopathy (CSM) and cervical spondylotic radiculopathy (CSR). However, there are relatively few studies on the relationship between apoptosis and CSA. As seen in the present study (Figs. 1,4), the lower the proportion of apoptotic cells, the more obvious the improvement of vertebral artery blood supply, so apoptosis may be a potential therapeutic target for CSA. Bax and Bcl-2 are often used to evaluate the extent of apoptosis [37, 38]. During apoptosis, the role of BAX is to induce apoptosis, contrary to bax, Bcl-2 inhibits cell apoptosis by forming a dimer with Bax) [39, 40]. Therefore, the key to determine apoptosis and survival is the ratio of Bcl-2 to Bax protein expression. The present study (Figs. 2,5) showed that massage treatment not only reduced the release of sympathetic neurotransmitters, but also increased the Bcl-2/Bax ratio in vertebral arteries and cerebella, indicating that massage can attenuate apoptosis induced by excessive ERS due to sympathetic excitation.
In summary, there may be a neuro-vascular regulatory mechanism in the treatment of CSA, and massage can improve vertebral artery blood flow and play a role in the treatment of CSA by relaxing the soft tissues of the neck, relieving the irritation of the sympathetic nerves caused by abnormal structure of the neck, reducing the release of sympathetic transmitters that constrict blood vessels, and alleviating apoptosis induced by excessive ERS due to sympathetic excitation. The changes in sympathetic excitability in this study were judged indirectly by its transmitter release, and further exploration can be done by adding the observation of heart rate, blood pressure, pupil, and monitoring of sympathetic discharge activity in subsequent studies. In addition, the process of apoptosis induced by ERS is more complex and involves multiple signaling pathways, which is one of the directions to explore the mechanism of massage for CSA in the future.