Biao Cheng

Sympathetic nerves: How do they affect angiogenesis, particularly during wound healing of soft tissues?

Angiogenesis is essential for wound healing, and angiogenesis impairment can result in chronic ulcers. Studies have shown that the sympathetic nervous system has an important role in angiogenesis. In recent years, researchers have focused on the roles of sympathetic nerves in tumor angiogenesis. In fact, sympathetic nerves can affect angiogenesis in the wound healing of soft tissues, and may have a similar mechanism of action as that seen in tumorigenesis. Sympathetic nerves act primarily through interactions between the neurotransmitters released from nerve endings and receptors present in target organs. Among this, activation or inhibition of adrenergic receptors (mainly β-adrenergic receptors) influence formation of new blood vessels considerably. As sympathetic nerves locate near pericytes in microvessel, go along the capillaries and there are adrenergic receptors present in endothelial cells and pericytes, sympathetic nerves may participate in angiogenesis by influencing the endothelial cells and pericytes of new capillaries. Studying the roles of sympathetic nerves on the angiogenesis of wound healing can contribute to understanding the mechanisms of tissue repair, tissue regeneration, and tumorigenesis, thereby providing new therapeutic perspectives.

Topical 1% propranolol cream promotes cutaneous wound healing in spontaneously diabetic mice

Diabetic foot ulcers (DFUs) are a constant threat to diabetic patients and can lead to amputations and even death. Intralesional administration of propranolol in diabetic wounds has not been reported previously. This study aimed to investigate the efficacy of propranolol cream in diabetic wounds. Fifty‐six spontaneously diabetic mice were divided into the propranolol group and the control group. After preparing full‐thickness wounds on the back of the mice, 1% propranolol cream was topically applied to wounds in the experimental group and 0% propranolol cream in controls. The wound sizes were measured and calculated against the original area. The wounds were analyzed up to 21 days after injury. At all evaluation time‐points, the wound size (%) in the propranolol group was significantly smaller than in the controls. Epidermal growth factor (EGF) protein expression increased in the experimental vs. control group. Vascular endothelial growth factor (VEGF) expression was significantly lower in the experimental vs. control group whereas NG2 proteoglycan was increased throughout the study. However, matrix metallopeptidase (MMP)‐9 expression was at first significantly higher in the experimental vs. control group then the MMP‐9 protein level in the control group increased and surpassed that in the experimental group. In conclusion, intralesional administration of 1% propranolol cream promotes reepithelialization and regulates abnormal angiogenesis in diabetic wounds. Propranolol cream may become a new drug for the treatment of DFUs.

Neurotensin-loaded PLGA/CNC composite nanofiber membranes accelerate diabetic wound healing

Abstract Diabetic foot ulcers (DFUs) are a threat to human health and can lead to amputation and even death. Recently neurotensin (NT), an inflammatory modulator in wound healing, was found to be beneficial for diabetic wound healing. As we demonstrated previously, polylactide–polyglycolide (PLGA) and cellulose nanocrystals (CNCs) (PLGA/CNC) nanofiber membranes show good cytocompatibility and facilitate fibroblast adhesion, spreading and proliferation. PLGA/CNC nanofiber membranes are novel materials that have not been used previously as NT carriers in diabetic wounds. This study aims to explore the therapeutic efficacy and possible mechanisms of NT-loaded PLGA/CNC nanofiber membranes in full-thickness skin wounds in spontaneously diabetic mice. The results showed that NT could be sustained released from NT-loaded PLGA/CNC composite nanofiber membranes for 2 weeks. NT-loaded PLGA/CNC composite nanofiber membranes induced more rapid healing than other control groups. After NT exposure, the histological scores of the epidermal and dermal regeneration and the ratios of the fibrotic area to the whole area were increased. NT-loaded PLGA/CNC composite nanofiber membranes also decreased the expressions of the inflammatory cytokines IL-1β and IL-6. These results suggest that NT-loaded PLGA/CNC composite nanofiber membranes for sustained delivery of NT should effectively promote tissue regeneration for the treatment of DFUs.

Sympathetic Denervation Accelerates Wound Contraction but Inhibits Reepithelialization and Pericyte Proliferation in Diabetic Mice

Previous studies focused on the effects of sympathetic denervation with 6-hydroxydopamine (6-OHDA) on nondiabetic wounds, but the effects of 6-OHDA on diabetic wounds have not been previously reported. In this study, treated mice received intraperitoneal 6-OHDA, and control mice received intraperitoneal injections of normal saline. Full-thickness wounds were established on the backs of mice. The wounds were sectioned (four mice per group) for analysis at 2, 5, 7, 10, 14, 17, and 21 days after injury. The wound areas in the control group were larger than those in the treatment group. Histological scores for epidermal and dermal regeneration were reduced in the 6-OHDA-treated group on day 21. The mast cells (MCs) in each field decreased after sympathectomy on days 17 and 21. The expression levels of norepinephrine, epidermal growth factor (EGF), interleukin-1 beta, NG2 proteoglycan, and desmin in the treatment group were less than those in the control group. In conclusion, 6-OHDA delays reepithelialization during wound healing in diabetic mice by decreasing EGF, but increases wound contraction by reducing IL-1β levels and the number of MCs. Besides, 6-OHDA led to reduced pericyte proliferation in diabetic wounds, which might explain the vascular dysfunction after sympathetic nerve loss in diabetic wounds.

The scalping forehead flap for 1-stage reconstruction of large facial defects after tumor resection.

AbstractSkin tumors often occur in the face or other sun-exposed areas in the aged population, and cancerous ulceration in the face leads to facial damage. Regarding the aesthetic character of the facial unit and the age or concomitant pathologies of these patients, it is necessary to use quick, reliable methods to debride malignant ulcer and cover the wound or suture the incision. We report 2 cases of large facial malignant ulcer that were treated with forehead flap based on the supratrochlear artery or the frontal branch of a side superficial temporal artery in a 1-stage operation. Both of them got satisfying functional and aesthetic results.

Recovery of sympathetic nerve function after lumbar sympathectomy is slower in the hind limbs than in the torso

Local sympathetic denervation by surgical sympathectomy is used in the treatment of lower limb ulcers and ischemia, but the restoration of cutaneous sympathetic nerve functions is less clear. This study aims to explore the recovery of cutaneous sympathetic functions after bilateral L2–4 sympathectomy. The skin temperature of the left feet, using a point monitoring thermometer, increased intraoperatively after sympathectomy. The cytoplasm of sympathetic neurons contained tyrosine hydroxylase and dopamine β-hydroxylase, visualized by immunofluorescence, indicated the accuracy of sympathectomy. Iodine starch test results suggested that the sweating function of the hind feet plantar skin decreased 2 and 7 weeks after lumbar sympathectomy but had recovered by 3 months. Immunofluorescence and western blot assay results revealed that norepinephrine and dopamine β-hydroxylase expression in the skin from the sacrococcygeal region and hind feet decreased in the sympathectomized group at 2 weeks. Transmission electron microscopy results showed that perinuclear space and axon demyelination in sympathetic cells in the L5 sympathetic trunks were found in the sympathectomized group 3 months after sympathectomy. Although sympathetic denervation occurred in the sacrococcygeal region and hind feet skin 2 weeks after lumbar sympathectomy, the skin functions recovered gradually over 7 weeks to 3 months. In conclusion, sympathetic functional recovery may account for the recurrence of hyperhidrosis after sympathectomy and the normalization of sympathetic nerve trunks after incomplete injury. The recovery of sympathetic nerve function was slower in the limbs than in the torso after bilateral L2–4 sympathectomy.

Phentolamine inhibits angiogenesis in vitro: Suppression of proliferation migration and differentiation of human endothelial cells.

It is widely known that the β-adrenergic receptor (AR) blocker (propranolol) inhibits human endothelial cell (EC) angiogenesis in vitro, but how the α-AR antagonist (phentolamine) affects human EC angiogenesis has not yet been studied. Here, we show for the first time that both human dermal microvascular ECs (HDMECs) and human brain microvascular ECs (HBMECs) express α-ARs. Moreover, our results indicate that phentolamine inhibits the proliferation, migration, and tubulogenesis of HDMECs and HBMECs. Finally, VEGFR-2 and Ang1/2 expression of HDMECs was suppressed by phentolamine. Together, these results indicate that phentolamine impairs several critical events of neovascularization, and α-ARs, as well as the VEGF/VEGFR-2 and Ang/Tie-2 signaling pathways, may be involved in these processes. Our results suggest a novel therapeutic strategy for the use of α-blockers in the treatment of human angiogenesis-dependent diseases.

Lumbar sympathectomy regulates vascular cell turnover in rat hindfoot plantar skin

BACKGROUND Sympathetic denervation and impaired angiogenesis cause skin diseases. However, the relationship between the sympathetic nervous system and vascular cell turnover in normal skin remains unclear. OBJECTIVE To determine the effects of sympathetic denervation on vascular cell turnover in normal skin. METHODS Rats underwent bilateral L2-4 sympathetic trunk resection (sympathectomy group) or sham operation (control). Hindfoot plantar skin was analyzed 2 weeks and 3 months postoperatively. RESULTS Mural cell marker (α-smooth muscle actin; p < 0.001, and desmin; p = 0.047) expression decreased 2 weeks after sympathectomy, but recovered 3 months after sympathectomy (p > 0.05). CD31 levels were lower in the experimental group than in the control group at 2 weeks (p = 0.009), but not at 3 months. Von Willebrand factor, vascular endothelial growth factor, and angiopoietin-2 expression were not significantly different between the groups (p > 0.05). Angiopoietin-1 expression levels were higher in the experimental group than in the control group at 2 weeks (p = 0.035), but not at 3 months. CONCLUSIONS Lumbar sympathectomy regulates vascular cell turnover in rat hindfoot plantar skin by inhibiting mural cell proliferation and increasing angiopoietin-1 expression. Sympathetic nerves therefore play an important role in plantar skin vascular cell turnover.

Norepinephrine Regulates Keratinocyte Proliferation to Promote the Growth of Hair Follicles

Psychological factors and stress can cause hair loss. The sympathetic-adrenal-medullary (SAM) axis has been reported to regulate the growth of hair follicles (HF). The sympathetic nerve is a component of the SAM axis, but it has not been sufficiently or convincingly linked to hair growth. In this study, we demonstrate that chemical sympathectomy via administration of the neurotoxin 6-hydroxydopamine (6-OHDA) to mice inhibited HF growth, but treatment with the β-adrenoceptor antagonist propranolol (PR) had no effect. HF length and skin thickness were greater in PR-treated and control mice than in 6-OHDA-treated mice, as evidenced by hematoxylin and eosin staining. Furthermore, we found that the reduced HF growth in sympathectomized animals was accompanied by a decreased keratinocyte proliferation. Moreover, the neurotransmitter norepinephrine (NE) was found to efficiently promote HF growth in an organotypic skin culture model. Together, these findings suggest that sympathetic nerves regulate keratinocyte behaviors to promote hair growth, providing novel insights into stress-related, chemotherapy-, and radiotherapy-induced alopecia.