[The functions of arterial sympathetic innervation: from development to pathology]. / Les fonctions de l'innervation sympathique artérielle - Du développement à la pathologie.

Arterial sympathetic innervation (ASI) is a complex biological process requiring a fine axonal guidance by arteries. Its physiological impact has remained unknown for decades but recently started to be better understood and recognized. ASI is a key element of the adaptive response of the cardiovascular system to challenging situations (exposure to cold, exercise…) as ASI controls the diameter of resistance arteries, thus blood supply to organs and systemic arterial blood pressure via arterial tone modulation. Defaults in ASI can lead to diseases, acting as a main cause or as an aggravating factor. Its impact is actively studied in cardiovascular diseases representing major public health issues, like hypertension, but ASI could also play a role in aging and many more pathological processes including cancer.

TITLE: Les fonctions de l'innervation sympathique artérielle - Du développement à la pathologie. ABSTRACT: L'innervation sympathique artérielle (ISA) est un processus biologique complexe nécessitant un guidage fin des axones des neurones sympathiques par les artères. L'ISA est un élément clé de l'adaptation du système cardiovasculaire aux différentes contraintes (exposition au froid, exercice, etc.) : elle contrôle le diamètre des artères de résistance, donc le flux sanguin parvenant aux organes et la pression artérielle systémique via la modulation du tonus artériel. Son importance lors du vieillissement et dans de nombreux contextes pathologiques est de mieux en mieux reconnue et comprise. Son intégration à la prise en charge de nombreuses maladies (hypertension, cancer, etc.) permettrait d'en améliorer traitements et pronostic.

Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins.

BACKGROUND: The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied. METHODS: We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α-induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene Bmal1 (also known as Arntl) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process. RESULTS: In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type-specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of ß2-adrenergic receptor signaling. Loss of the core clock gene Bmal1 in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type-specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence. CONCLUSIONS: Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day-dependent vessel type-specific thrombotic events.

A systematic review on persistent trigeminal artery, in searching for a therapeutic solution to idiopathic and unresponsive trigeminal nerve inflammations and migraines.

The rarely diagnosed persistent trigeminal artery (PTA) originates from the posterior bend or lateral wall of the intracavernous carotid artery and is the most common occurring type of remnant primitive fetal arteries. Even if PTA is uncommon, information and awareness about it could be of great help for clinicians dealing with cranial vascular imaging and operating this region. In addition, it could give a supporting response to the presence of a wide range of idiopathic and unresponsive disturbs that sometimes are erroneously interpreted and treated. There are very few published scientific reports of coexisting PTA and unilateral trigeminal neuralgia and migraine-cephalgia (MC). In this review we describe few reported and unreported cases regarding the manifestation of unresponsive trigeminal neuralgia and migraine due to the presence of PTA. Patients usually present with a clinical symptomatology with unstable blood hypertension, pain of typical trigeminal neuralgia and MC that cover unilaterally the occipital area over the second and third divisions of the nerve. The outbreaks may often become more severe during physical exertion, stress and hypertension. Angio-MRI may reveal the PTA with an occasional occurrence of parietal cavernoma. We also describe a case of chronic left MC case associated with an adjacent PTA close to the trigeminal nerve position. The size and location of the PTA was confirmed by a CT-Angiography. The MC was safely treated by bio-identical testosterone, human placenta extract (HPE), b-nicotinamide adenine dinucleotide (NADH) and low dose amlopidine. It is hypothesized that these types of primitive anastomose arteries that fully belong to the intracranial arterial vascular system do not perform any supportive functional activity. Nevertheless, they undergo the normal biological decay caused by the aging process and metabolic dysfunctions. Therefore, such primitive fetal arteries as PTA might be subjected not only to a faster structural deterioration but they would actively contribute to a series of mechanisms causing a variety of idiopathic intracranial vascular and structural symptoms. Consequently, this would change the primary therapeutic approach to solve this problem, today represented by surgical removal. Anatomic implications related to treatment procedure are also discussed.

Peri-arterial Autonomic Innervation of the Human Ear.

Auricular vasomotor responses are considered to be signs of clinical conditions including migraine. The mechanisms of auricular vasomotor control are still debatable. This study aimed at investigating perivascular co-transmitters of vasomotor control in the auricle. Another aim was to provide three-dimensional arterial maps of the auricle, as a proxy of periarterial autonomic innervation. Twelve paired human auricles were used to visualize the arteries following Spalteholz clearing and µ-CT-based reconstruction. Perivascular innervation staining was conducted using anti-tyrosine hydroxylase (TH), anti-neuropeptide Y (NPY), anti-vasoactive intestinal peptide (VIP) and anti-choline acetyl transferase (ChAT). The combined Spalteholz technique and µ-CT revealed a highly consistent arrangement of the auricular vasculature. The superficial temporal (STA) and posterior auricular artery (PAA) supply the helical rim arcade and arcade, with the STA mainly forming the superior and the PAA forming the middle and inferior auricular artery. Co-existence of sympathetic NPY+ and TH+ terminals mediating vasoconstriction, and VIP+ and ACh+ indicating cholinergic vasodilatation, was found in the perivascular zone. The presence of both sympathetic vasoconstriction and cholinergic co-innervation for active vasodilatation was shown in the perivascular auricular zone. Assuming that the highly-consistent vasculature gives way to these terminals, this periarterial innervation may be found spread out across the helix.

Patterns of sural nerve innervation of the sural artery with implication for reconstructive surgery.

BACKGROUND: Most of the literature concerning the neurocutaneous flap is related to its anatomic investigation and clinical application, and the more in-depth physiological problem such as whether the cutaneous nerve contains sympathetic fibers that innervate its accompanying vessels has never been explored. MATERIALS AND METHODS: Dissection was first performed on three rabbits. In another 22 rabbits, two rabbits undergoing no surgery were used as the normal control group. In the remaining 20 rabbits, the 40 sides of hind limbs were divided into a nerve severance group, where the sural nerve was transected at its origin after creation of the proximally based sural neurocutaneous flap, and a nerve preservation group, in which the continuation of the sural nerve was preserved. The sural neurovascular bundles at four time points were harvested for immunohistochemical and Western blotting analyses of the expression of tyrosine hydroxylase (TH). An infrared thermal imager was used for measurement of the average flap temperature within the first 24 h. RESULTS: The sural neurovascular bundle entered the skin at 4.5 ± 1.2 cm above the lateral malleolus. The TH in the sural nerve and tunica adventitia of the sural artery showed a synchronized abated expression in the nerve severance group. The TH expression showed no decline in the nerve preservation group. The average flap temperature in the nerve severance group was higher than that in the nerve preservation group starting from 2 h after flap harvest (P = 0.05). CONCLUSIONS: The cutaneous nerve has meted out sympathetic fibers to the accompanying artery, regulating its vascular tone.

Relationship between Vascular Resistance and Sympathetic Nerve Fiber Density in Arterial Vessels in Children With Sleep Disordered Breathing.

BACKGROUND: Sleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early-onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans. METHODS AND RESULTS: Thirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow-mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral (r=0.63; P<0.05) and a lower Neuronal Pupillary Index (r=-0.71, P<0.01), as well as a slower mean pupillary constriction velocity (mean, r=-0.64; P<0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity (r=-0.77; P<0.01) and higher platelet aggregation to collagen antigen (r=0.64; P<0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores (P<0.05; P<0.01, respectively). CONCLUSIONS: These results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing.

Digital periarterial sympathectomy in the management of post-traumatic Raynaud syndrome.

OBJECTIVE: Among Basque handball players, the repeated impact of a ball on the palms of their hands hundreds of thousands of times throughout their sporting careers produces Raynaud syndrome. Treating this patient group is complex. Our objective was to assess the efficacy of digital periarterial sympathectomy in this patient group. METHODS: The study included all of the federated amateur and professional Basque handball patients who presented with Raynaud syndrome assessed in the vascular surgery service between January 2005 and December 2012. The postoperative assessment included a physical examination, basal photoplethysmography and photoplethysmography after heat hyperemia, and arteriography or magnetic resonance angiography. RESULTS: All 182 digital periarterial sympathectomies in the 114 fingers of 60 patients were in Porter functional class III or IV. All patients were discharged within the first 48 hours. Follow-up results, with a mean of 2 years ± 5 months, were 100%. All patients presented immediate pain remission, recovery of comfort, normal nail growth, rapid healing of all ulcers, distal anhidrosis, and return to active sport participation. The results remain steady in 58 patients (93.5%). Mean time until return to sports activity was 9.95 ± 1.61 weeks. CONCLUSIONS: Digital periarterial sympathectomy is a simple, relatively nonaggressive technique without adverse side effects and with excellent medium-term results. In patients with Raynaud syndrome refractory to medical treatment and with threat to the viability of one or several fingers, digital periarterial sympathectomy can be the first treatment option, especially in cases of arteritis associated with very severe spasms.

[Efficacy observation on repair of finger pulp defects and sensory reconstruction of children with the perforator propeller flaps based on the end dorsal branch of digital proper artery in the same finger].

OBJECTIVE: To investigate the clinical outcomes of the use of the perforator propeller flaps based on the end dorsal branch of digital proper artery in the same finger in repair of finger pulp defects and sensory reconstruction in children. METHODS: Twenty-three children (31 fingers) with index, middle, ring or little finger pulp defects were hospitalized from September 2012 to December 2013. The area of finger pulp defects ranged from 1.2 cm × 1.0 cm to 2.0 cm × 1.5 cm. The perforator propeller flaps based on the end dorsal branch of digital proper artery in the same finger were used to repair the defects, with the flap size ranging from 1.3 cm × 1.2 cm to 2.2 cm × 1.6 cm. The dorsal branch of the digital proper nerve of the flap was conducted end-to-end anastomosis with the broken end of the nerve of the wound to reconstruct sensation. The donor sites were covered with autologous full-thickness skin obtained from inner aspect of the thigh. RESULTS: Primary healing of the wounds and donor sites were achieved in all 23 children. All the flaps and skin grafts of donor sites survived. All the patients were followed up for 6 to 20 months, with mean time of 14 months. At the last follow-up, the flaps and donor sites were in good appearance, the finger pulps were mellow and plump, with no obvious pigmentation or cicatricial contracture. The sensation of finger pulps reached S3(+), and the distance of two-point discrimination ranged from 4.5 to 6.0 mm, with mean distance of 5.1 mm. Twenty-one parents of the patients were strongly satisfied with the appearance of the repaired fingers, and the other 2 parents also expressed satisfaction. CONCLUSIONS: Transplantation of the perforator propeller flap based on the end dorsal branch of digital proper artery in the same finger is a safe and reliable method for the repair of index, middle, ring, and little finger pulp defects and sensory reconstruction of children. The flaps are with good blood supply, appearance and sensory function after operation.

Differences in control of parasympathetic vasodilation between submandibular and sublingual glands in the rat.

We examined blood flow in the submandibular gland (SMGBF) and sublingual gland (SLGBF) during electrical stimulation of the central cut end of the lingual nerve (LN) in the urethane-anesthetized rats using a laser speckle imaging flow meter. LN stimulation elicited intensity- and frequency-dependent SMGBF and SLGBF increases, and the magnitude of the SMGBF increase was higher than that of the SLGBF increase. The increase in both glands was significantly inhibited by intravenous administration of the autonomic cholinergic ganglion blocker hexamethonium. The antimuscarinic agent atropine markedly inhibited the SMGBF increase and partly inhibited the SLGBF increase. The atropine-resistant SLGBF increase was significantly inhibited by infusion of vasoactive intestinal peptide (VIP) receptor antagonist, although administration of VIP receptor antagonist alone had no effect. The recovery time to the basal blood flow level was shorter after LN stimulation than after administration of VIP. However, the recovery time after LN stimulation was significantly delayed by administration of atropine in a dose-dependent manner to the same level as after administration of VIP. Our results indicate that 1) LN stimulation elicits both a parasympathetic SMGBF increase mainly evoked by cholinergic fibers and a parasympathetic SLGBF increase evoked by cholinergic and noncholinergic fibers, and 2) VIP-ergic mechanisms are involved in the noncholinergic SLGBF increase and are activated when muscarinic mechanisms are deactivated.

Distribution and innervation of putative peripheral arterial chemoreceptors in the red-eared slider (Trachemys scripta elegans).

Peripheral arterial chemoreceptors have been isolated to the common carotid artery, aorta, and pulmonary artery of turtles. However, the putative neurotransmitters associated with these chemoreceptors have not yet been described. The goal of the present study was to determine the neurochemical content, innervations, and distribution of putative oxygen-sensing cells in the central vasculature of turtles and to derive homologies with peripheral arterial chemoreceptors of other vertebrates. We used tract tracing together with immunohistochemical markers for cholinergic cells (vesicular acetylcholine transporter [VAChT]), tyrosine hydroxylase (TH; the rate-limiting enzyme in catecholamine synthesis), and serotonin (5HT) to identify putative oxygen-sensing cells and to determine their anatomical relation to branches of the vagus nerve (Xth cranial nerve). We found potential oxygen-sensing cells in all three chemosensory areas innervated by branches of the Xth cranial nerve. Cells containing either 5HT or VAChT were found in all three sites. The morphology and size of these cells resemble glomus cells found in amphibians, mammals, tortoises, and lizards. Furthermore, we found populations of cholinergic cells located at the base of the aorta and pulmonary artery that are likely involved in efferent regulation of vessel resistance. Catecholamine-containing cells were not found in any of the putative chemosensitive areas. The presence of 5HT- and VAChT-immunoreactive cells in segments of the common carotid artery, aorta, and pulmonary artery appears to reflect a transition between cells containing the major neurotransmitters seen in fish (5HT) and mammals (ACh and adenosine).

Novel vasocontractile role of the P2Y14 receptor: characterization of its signalling in porcine isolated pancreatic arteries.

BACKGROUND AND PURPOSE: The P2Y14 receptor is the newest member of the P2Y receptor family; it is G(i/o) protein-coupled and is activated by UDP and selectively by UDP-glucose and MRS2690 (2-thiouridine-5'-diphosphoglucose) (7-10-fold more potent than UDP-glucose). This study investigated whether P2Y14 receptors were functionally expressed in porcine isolated pancreatic arteries. EXPERIMENTAL APPROACH: Pancreatic arteries were prepared for isometric tension recording and UDP-glucose, UDP and MRS2690 were applied cumulatively after preconstriction with U46619, a TxA2 mimetic. Levels of phosphorylated myosin light chain 2 (MLC2) were assessed with Western blotting. cAMP concentrations were assessed using a competitive enzyme immunoassay kit. KEY RESULTS: Concentration-dependent contractions with a rank order of potency of MRS2690 (10-fold) > UDP-glucose ≥ UDP were recorded. These contractions were reduced by PPTN {4-[4-(piperidin-4-yl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthoic acid}, a selective antagonist of P2Y14 receptors, which did not affect responses to UTP. Contraction to UDP-glucose was not affected by MRS2578, a P2Y6 receptor selective antagonist. Raising cAMP levels and forskolin, in the presence of U46619, enhanced contractions to UDP-glucose. In addition, UDP-glucose and MRS2690 inhibited forskolin-stimulated cAMP levels. Removal of the endothelium and inhibition of endothelium-derived contractile agents (TxA2, PGF(2α) and endothelin-1) inhibited contractions to UDP glucose. Y-27632, nifedipine and thapsigargin also reduced contractions to the agonists. UDP-glucose and MRS2690 increased MLC2 phosphorylation, which was blocked by PPTN. CONCLUSIONS AND IMPLICATIONS: P2Y14 receptors play a novel vasocontractile role in porcine pancreatic arteries, mediating contraction via cAMP-dependent mechanisms, elevation of intracellular Ca²âº levels, activation of RhoA/ROCK signalling and MLC2, along with release of TxA2, PGF(2α) and endothelin-1.

True and 'choke' anastomoses between perforator angiosomes: part i. anatomical location.

BACKGROUND: Reports of more than two cutaneous perforator angiosome territories being raised successfully in distally based sural flaps are appearing in the literature. Previous anatomical studies have noted that cutaneous arteries, connected by true anastomosis without change in caliber, frequently parallel cutaneous nerves. METHODS: Twenty-four (48 sides) total body lead oxide cadaver injection studies, including seven arterial and two venous neurovascular, were examined, and the results were compared with clinical thermography in Part II. RESULTS: Long branches of cutaneous perforators, connected in a series by true anastomoses, paralleled at variable distances the main trunks of cutaneous nerves in the head, neck, torso, and upper and lower extremities. Specifically, in the leg, an average of 3.2 true anastomoses (range, 1 to 5) connected perforators that paralleled the sural nerve on the back of the calf; and 2.5 (range, 1 to 4) connected perforators on the medial side of the leg. These vascular freeways were paralleled by the short and long saphenous veins, respectively. CONCLUSIONS: True anastomoses frequently connect skin perforators that course in parallel with cutaneous nerves and veins. They provide an explanation for the long viable flaps noted in the leg, and it will be shown in Part II that they can be detected preoperatively with thermography.

Long-term results of arterial sympathectomy and artery reconstruction with vein bypass technique as a salvage procedure for severe digital ischemia.

The aim of this study is to present a combined treatment of arterial sympathectomy and artery reconstruction with vein bypass technique in patients with severe digital ischemia. In all, 22 patients representing 53 digits received treatment during a 15-year period. Skin color and trophic changes including ulcers, necrosis, and amputation; pain level according to the visual analog scale; and functional assessment based on the disabilities of the arm, shoulder, and hand questionnaire were recorded. After surgery, the skin discoloration improved, and the trophic changes healed in the majority of patients. Amputation was required in 2 cases. Pain and function improved significantly postoperatively. Based on the results of this study, vascular reconstruction combined with sympathectomy may be indicated on an individualized basis for patients with digital ischemia. This procedure can lead to healing of skin trophic changes, diminution of pain, avoidance of amputation, and long-term improvement in life quality.

New insights into the effects of age and sex on arterial baroreflex function at rest and during dynamic exercise in humans.

The arterial baroreflex (ABR) performs an important role in regulating blood pressure (BP) both at rest and during exercise, by carefully orchestrating autonomic neural activity to the heart and blood vessels. Reduced ABR sensitivity (i.e., gain) has been associated with increased cardiovascular risk, cardiac electrical instability and orthostatic intolerance, while 'normal' ABR function during exercise is important for ensuring an appropriate cardiovascular response is elicited. Previous studies examining the influence of age and sex on resting ABR function in humans have primarily used pharmacological methods (e.g., modified Oxford technique) to change BP and alter baroreceptor input. With this approach only reflex control of heart rate and sympathetic nerve activity may be evaluated, and as such the influence of age and sex on ABR control of BP per se remains incompletely understood. Furthermore, the majority of previous studies examining ABR function during exercise have principally assessed young men. Whether these findings can be extrapolated to young women or older men and women remains unclear. Recently the potential for age and sex to modulate the integrative neural control of the cardiovascular system is becoming appreciated. This review article will provide a detailed update of such recent advances into our understanding of the effects of age and sex on ABR control of BP both at rest and during dynamic exercise in humans.

Dysfunction of neurotransmitter modulation system on adrenergic nerves of caudal artery in type 2 diabetic Goto-Kakizaki rats.

The Goto-Kakizaki (GK) rat is a non-obese and spontaneous model of mild Type 2 diabetes mellitus. In the present study, we compared the regulatory mechanisms of endogenous norepinephrine (NE) release from sympathetic nerves of caudal arteries of 12-week-old GK rats and age-matched normal Wistar rats. Electrical stimulation (ES) evoked significant NE release from caudal arteries of Wistar and GK rats. The amounts of NE released by ES were almost equal in Wistar and GK rats, although the NE content in caudal artery of GK rats was significantly lower than that of Wistar rats. We examined the effects of an α2-adrenoceptor agonist, clonidine (CLO), and an α2-adrenoceptor antagonist, yohimbine (YOH), on the release of endogenous NE evoked by ES. CLO significantly reduced NE release from caudal arteries of Wistar but not GK rats. On the other hand, YOH significantly increased NE release from both rats. Furthermore, we examined the effects of an A1-adenosine receptor agonist, 2-chloroadenosine (2CA), and an A1-adenosine receptor antagonist, 8-sulfophenyltheophylline (8SPT), on the release of endogenous NE evoked by ES. 2CA significantly reduced NE release from caudal arteries of Wistar but not GK rats. On the other hand, 8SPT did not affect NE release from both rats. These results suggest that the dysfunction of negative feedback regulation of NE release via presynaptic receptors on sympathetic nerves in GK rats may be involved in the autonomic nervous system dysfunction associated with diabetic autonomic neuropathy.

Nitrergic nerves derived from the pterygopalatine ganglion innervate arteries irrigating the cerebrum but not the cerebellum and brain stem in monkeys.

The functional roles of the nitrergic nerves innervating the monkey cerebral artery were evaluated in a tension-response study examining isolated arteries in vitro and cerebral angiography in vivo. Nicotine produced relaxation of arteries by stimulation of nerve terminals innervating isolated monkey arteries irrigating the cerebrum, cerebellum and brain stem. Relaxation of arteries induced by nicotine was abolished by treatment with N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor, and was restored by addition of L-arginine. Cerebral angiography showed that electrical stimulation of the unilateral greater petrosal nerve, which connects to the pterygopalatine ganglion via the parasympathetic ganglion synapse, produced vasodilatation of the anterior, middle and posterior cerebral arteries in the stimulated side. However, stimulation failed to produce vasodilatation of the superior and anterior-inferior cerebellar arteries and the basilar artery in anesthetized monkeys. Therefore, nitrergic nerves derived from the pterygopalatine ganglion appear to regulate cerebral vasomotor function. In contrast, circulation in the cerebellum and brain stem might be regulated by nitrergic nerves originating not from the pterygopalatine ganglion, but rather from an unknown ganglion (or ganglia).