Focused ultrasound excites action potentials in mammalian peripheral neurons in part through the mechanically gated ion channel PIEZO2.

Neurons of the peripheral nervous system (PNS) are tasked with diverse roles, from encoding touch, pain, and itch to interoceptive control of inflammation and organ physiology. Thus, technologies that allow precise control of peripheral nerve activity have the potential to regulate a wide range of biological processes. Noninvasive modulation of neuronal activity is an important translational application of focused ultrasound (FUS). Recent studies have identified effective strategies to modulate brain circuits; however, reliable parameters to control the activity of the PNS are lacking. To develop robust noninvasive technologies for peripheral nerve modulation, we employed targeted FUS stimulation and electrophysiology in mouse ex vivo skin-saphenous nerve preparations to record the activity of individual mechanosensory neurons. Parameter space exploration showed that stimulating neuronal receptive fields with high-intensity, millisecond FUS pulses reliably and repeatedly evoked one-to-one action potentials in all peripheral neurons recorded. Interestingly, when neurons were classified based on neurophysiological properties, we identified a discrete range of FUS parameters capable of exciting all neuronal classes, including myelinated A fibers and unmyelinated C fibers. Peripheral neurons were excited by FUS stimulation targeted to either cutaneous receptive fields or peripheral nerves, a key finding that increases the therapeutic range of FUS-based peripheral neuromodulation. FUS elicited action potentials with millisecond latencies compared with electrical stimulation, suggesting ion channel­mediated mechanisms. Indeed, FUS thresholds were elevated in neurons lacking the mechanically gated channel PIEZO2. Together, these results demonstrate that transcutaneous FUS drives peripheral nerve activity by engaging intrinsic mechanotransduction mechanisms in neurons [B. U. Hoffman, PhD thesis, (2019)].

[Seasonal changes in blood pressure and related factors among older patients receiving home medical care].

AIM: We investigated seasonal variations in blood pressure (BP) and factors related to these variations among older patients receiving home medical care. METHOD: A total 57 patients ≥ 65 years old receiving home medical care who participated in the Osaka Home Care REgistry study (OHCARE), a prospective cohort study, were included. We investigated the seasonal patient characteristics and variations in the BP. In addition, to determine the influence of seasonal variations in the systolic blood pressure (SBP) on the occurrence of clinical events (hospitalization, falls and death), we classified patients into larger- and smaller- change groups based on the median seasonal variations in SBP. RESULT: About 60% of subjects were very frail or bedridden. The mean BP was higher in winter than in summer (124.7±11/69.5±7 vs.120.5±12/66.9±8 mmHg) (P< 0.01). On comparing the characteristics of the two groups with larger and smaller changes in the SBP, the group with large BP changes had a significantly lower BP in summer than the group with small BP changes. In addition, the incidence of "hospitalization" was significantly higher in the group with large BP changes than in the group with small BP changes (P = 0.03). CONCLUSION: The present study revealed that there were seasonal changes in the BP in older patients receiving home medical care. It was also suggested that seasonal changes in the BP might be associated with the risk of hospitalization events. Given these BP variations, doctors and visiting nurses should be alert for systemic abnormalities, especially in frail patients receinving home medical care.

Piezo2 is required for Merkel-cell mechanotransduction.

How we sense touch remains fundamentally unknown. The Merkel cell-neurite complex is a gentle touch receptor in the skin that mediates slowly adapting responses of Aß sensory fibres to encode fine details of objects. This mechanoreceptor complex was recognized to have an essential role in sensing gentle touch nearly 50 years ago. However, whether Merkel cells or afferent fibres themselves sense mechanical force is still debated, and the molecular mechanism of mechanotransduction is unknown. Synapse-like junctions are observed between Merkel cells and associated afferents, and yet it is unclear whether Merkel cells are inherently mechanosensitive or whether they can rapidly transmit such information to the neighbouring nerve. Here we show that Merkel cells produce touch-sensitive currents in vitro. Piezo2, a mechanically activated cation channel, is expressed in Merkel cells. We engineered mice deficient in Piezo2 in the skin, but not in sensory neurons, and show that Merkel-cell mechanosensitivity completely depends on Piezo2. In these mice, slowly adapting responses in vivo mediated by the Merkel cell-neurite complex show reduced static firing rates, and moreover, the mice display moderately decreased behavioural responses to gentle touch. Our results indicate that Piezo2 is the Merkel-cell mechanotransduction channel and provide the first line of evidence that Piezo channels have a physiological role in mechanosensation in mammals. Furthermore, our data present evidence for a two-receptor-site model, in which both Merkel cells and innervating afferents act together as mechanosensors. The two-receptor system could provide this mechanoreceptor complex with a tuning mechanism to achieve highly sophisticated responses to a given mechanical stimulus.

Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors.

Touch submodalities, such as flutter and pressure, are mediated by somatosensory afferents whose terminal specializations extract tactile features and encode them as action potential trains with unique activity patterns. Whether non-neuronal cells tune touch receptors through active or passive mechanisms is debated. Terminal specializations are thought to function as passive mechanical filters analogous to the cochlea's basilar membrane, which deconstructs complex sounds into tones that are transduced by mechanosensory hair cells. The model that cutaneous specializations are merely passive has been recently challenged because epidermal cells express sensory ion channels and neurotransmitters; however, direct evidence that epidermal cells excite tactile afferents is lacking. Epidermal Merkel cells display features of sensory receptor cells and make 'synapse-like' contacts with slowly adapting type I (SAI) afferents. These complexes, which encode spatial features such as edges and texture, localize to skin regions with high tactile acuity, including whisker follicles, fingertips and touch domes. Here we show that Merkel cells actively participate in touch reception in mice. Merkel cells display fast, touch-evoked mechanotransduction currents. Optogenetic approaches in intact skin show that Merkel cells are both necessary and sufficient for sustained action-potential firing in tactile afferents. Recordings from touch-dome afferents lacking Merkel cells demonstrate that Merkel cells confer high-frequency responses to dynamic stimuli and enable sustained firing. These data are the first, to our knowledge, to directly demonstrate a functional, excitatory connection between epidermal cells and sensory neurons. Together, these findings indicate that Merkel cells actively tune mechanosensory responses to facilitate high spatio-temporal acuity. Moreover, our results indicate a division of labour in the Merkel cell-neurite complex: Merkel cells signal static stimuli, such as pressure, whereas sensory afferents transduce dynamic stimuli, such as moving gratings. Thus, the Merkel cell-neurite complex is an unique sensory structure composed of two different receptor cell types specialized for distinct elements of discriminative touch.

[Factors associated with behavioral and psychological symptoms in patients with dementia who received home medical treatment: A cross-sectional study (OHCARE study)].

AIM: The present study investigated the behavioral and psychological symptoms of dementia (BPSD) and pharmacological therapy among elderly people with dementia who received home medical treatment. METHODS: This study was part of the Osaka Home Care Registry study (OHCARE-study). Participants were >65 years old with dementia. Demographic and medical data, BPSD, and the LTCI [long-term care insurance] care-need level were collected. A multiple logistic regression analysis was performed in order to clarify the factors associated with BPSD. RESULTS: Among 110 subjects (82.0±11.3 years old), 64.6% had a diagnosis of dementia, most commonly Alzheimer's dementia. Aside from home medical treatment, 58.1% had a nurse visit, 48.1% received home care, and 40.0% used a day service. The prevalence of BPSD was 53.0%. Those with BPSD most frequently had an LTCI care-need level of 3, and the prevalence of BPSD declined as the level increased after 3. Psychotropic drugs were prescribed in 61.5% of those with BPSD. Antipsychotic drugs were used significantly more frequently in those with nursing care resistance, assault and delusions than in others (all, p <0.005). A multivariate analysis showed that the positive predictor of BPSD was antipsychotic drug use, while negative predictors were an LTCI care-need level and the use of visiting rehabilitation. CONCLUSION: The BPSD in elderly dementia patients receiving home medical treatment were clarified. The LTCI care-need level is an independent predictor of BPSD after adjusting for the activities of daily life. Further longitudinal investigations including the BPSD severity and frequency are needed.

Computational modeling indicates that surface pressure can be reliably conveyed to tactile receptors even amidst changes in skin mechanics.

Distinct patterns in neuronal firing are observed between classes of cutaneous afferents. Such differences may be attributed to end-organ morphology, distinct ion-channel complements, and skin microstructure, among other factors. Even for just the slowly adapting type I afferent, the skin's mechanics for a particular specimen might impact the afferent's firing properties, especially given the thickness and elasticity of skin can change dramatically over just days. Here, we show computationally that the skin can reliably convey indentation magnitude, rate, and spatial geometry to the locations of tactile receptors even amid changes in skin's structure. Using finite element analysis and neural dynamics models, we considered the skin properties of six mice that span a representative cohort. Modeling the propagation of the surface stimulus to the interior of the skin demonstrated that there can be large variance in stresses and strains near the locations of tactile receptors, which can lead to large variance in static firing rate. However, variance is significantly reduced when the stimulus tip is controlled by surface pressure and compressive stress is measured near the end organs. This particular transformation affords the least variability in predicted firing rates compared with others derived from displacement, force, strain energy density, or compressive strain. Amid changing skin mechanics, stimulus control by surface pressure may be more naturalistic and optimal and underlie how animals actively explore the tactile environment.

Mechanotransduction in epidermal Merkel cells.

The cellular and molecular basis of vertebrate touch reception remains least understood among the traditional five senses. Somatosensory afferents that innervate the skin encode distinct tactile qualities, such as flutter, slip, and pressure. Gentle touch is thought to be transduced by somatosensory afferents whose tactile end organs selectively filter mechanical stimuli. These tactile end organs comprise afferent terminals in association with non-neuronal cell types such as Merkel cells, keratinocytes, and Schwann cells. An open question is whether these non-neuronal cells serve primarily as passive mechanical filters or whether they actively participate in mechanosensory transduction. This question has been most extensively studied in Merkel cells, which are epidermal cells that complex with sensory afferents in regions of high tactile acuity such as fingertips, whisker follicles, and touch domes. Merkel cell-neurite complexes mediate slowly adapting type I (SAI) responses, which encode sustained pressure and represent object features with high fidelity. How Merkel cells contribute to unique SAI firing patterns has been debated for decades; however, three recent studies in rodent models provide some direct answers. First, whole-cell recordings demonstrate that Merkel cells are touch-sensitive cells with fast, mechanically activated currents that require Piezo2. Second, optogenetics and intact recordings show that Merkel cells mediate sustained SAI firing. Finally, loss-of-function studies in transgenic mouse models reveal that SAI afferents are also touch sensitive. Together, these studies identify molecular mechanisms of mechanotransduction in Merkel cells, reveal unexpected functions for these cells in touch, and support a revised, two-receptor site model of mechanosensory transduction.

Excitatory glutamate is essential for development and maintenance of the piloneural mechanoreceptor.

The piloneural collar in mammalian hairy skin comprises an intricate pattern of circumferential and longitudinal sensory afferents that innervate primary and secondary pelage hairs. The longitudinal afferents tightly associate with terminal Schwann cell processes to form encapsulated lanceolate nerve endings of rapidly adapting mechanoreceptors. The molecular basis for piloneural development, maintenance and function is poorly understood. Here, we show that Nefh-expressing glutamatergic neurons represent a major population of longitudinal and circumferential sensory afferents innervating the piloneural collar. Our findings using a VGLUT2 conditional-null mouse model indicate that glutamate is essential for innervation, patterning and differentiation of NMDAR(+) terminal Schwann cells during piloneural collar development. Similarly, treatment of adult mice with a selective NMDAR antagonist severely perturbed piloneural collar structure and reduced excitability of these mechanosensory neurons. Collectively, these results show that DRG-derived glutamate is essential for the proper development, maintenance and sensory function of the piloneural mechanoreceptor.

Actual conditions for returning home after hospitalization among older patients receiving home medical care in Japan: OHCARE Study.

AIM: To examine the actual conditions of older patients receiving home medical care after hospitalization over a period of 2 years in Japan. METHODS: The study population included 102 participants, aged ≥65 years, receiving home medical care, who consented to participate in the Osaka Home Care Registry (OHCARE) study in Japan over a period of 2 years. We investigated the actual conditions for returning home after hospitalization. RESULTS: The median age of the 102 participants was 84 years, and 61 (59.8%) were women. In the group that returned home, 42 (55.3%) of the respondents desired to recuperate in a familiar place, as in advanced care planning (ACP). During the 2-year follow-up period, the group that did not return home had significantly more deaths. A multivariate analysis showed the association in the presence of ACP (odds ratio: 4.72, 95% confidence interval: 1.60-13.86) and cardiac disease (odds ratio: 0.25, 95% confidence interval: 0.08-0.76). The lack of ACP in the medical records when the patient was admitted to the hospital may have prevented the return home. CONCLUSION: In older patients who had difficulty returning home after hospitalization, the lack of ACP in home medical care may have been an influencing factor. ACP could help continue with home medical care. Geriatr Gerontol Int 2024; 24: 320-326.

Usefulness of the resistive index in renal Doppler ultrasonography as an indicator of vascular damage in patients with risks of atherosclerosis.

BACKGROUND: Chronic kidney disease (CKD) is caused by various risk factors of cardiovascular disease (CVD). The estimated glomerular filtration rate (eGFR) is commonly used for the evaluation of the renal function in patients with CKD; however, it is difficult to assess the pathogenesis of CKD and predict the renal prognosis accurately using only eGFR. The resistive index (RI) in renal Doppler ultrasonography (RDU) is thought to be a good indicator of renal vascular resistance caused by atherosclerosis. In the present study, we investigated whether RI could be used to evaluate the pathogenesis of renal damage and predict the renal prognosis and investigated the correlation between RI and blood pressure (BP) fluctuations in patients with or without hypertension. METHODS: The total study population included 194 patients (mean age: 66.2 years), who underwent RDU in our hospital ward between February 2009 and July 2010. We investigated the correlation between RI and multiple clinical parameters, including ambulatory blood pressure monitoring (ABPM). RESULTS: RI significantly correlated with age, eGFR, diastolic BP, pulse pressure and level of albuminuria. Patients with diabetes mellitus (DM) showed a significantly higher RI than patients without DM, although their eGFR was similar; thus, DM might accelerate renal vascular damage and RI could detect earlier changes of vascular damage proceeding the time eGFR is reduced. Regarding ABPM, patients with a larger morning surge [systolic blood pressure (SBP) in the early morning--lowest SBP during sleep] showed a significantly higher RI. CONCLUSIONS: The present study indicated that RI might be very useful for the evaluation of very early renal damage more effectively than eGFR and that diurnal BP change might be partly due to the progression of atherosclerotic change in the kidney evaluated by RI.

Associations of blood pressure levels with clinical events in older patients receiving home medical care.

Some studies reported that excessive blood pressure (BP) control was not appropriate for older people, especially from the viewpoint of quality of life and maintaining sufficient blood flow for tissue perfusion. However, the lower limit of the target BP is still unclear, and there has not yet been a sufficient consensus. Therefore, we investigated the associations of BP levels with clinical events in older patients ~85 years old receiving home medical care. A total of 144 patients were included, who were followed for longer than 3 months in the Osaka Home Care Registry study, a prospective cohort study targeting older patients receiving home medical care in Japan. BP levels were divided into lower and higher groups based on the average systolic blood pressure (SBP). The main outcomes were clinical events, including hospitalizations, falls, and deaths during follow-up. As a result, the hospitalization rate in the SBP below 124 mmHg group was significantly higher than that in the SBP over 124 mmHg group. When comparing the clinical events between the two groups only in participants with hypertension, the same results were obtained. Furthermore, in Cox proportional hazards regression models adjusted by age, sex, and current diseases, the SBP below 124 mmHg group showed a significantly higher rate of required hospitalization (hazard ratio: 7.25, 95% confidence interval: 1.79-29.45). Thus, in older and very frail patients requiring home medical care, an SBP level below 124 mmHg could be a predictive marker of clinical events leading to hospitalization.

Collision avoidance by running insects: antennal guidance in cockroaches.

Cockroaches were observed with videographic methods as escape running was initiated, but with obstacles in the path of their run. The goal was to determine the repertoire of possible responses to obstacles and the sensory cues used to trigger the responses. Intact cockroaches collided with obstacles on only about 10% of trials. The most common collision avoidance strategy was simply to stop running prior to impact. However, occasionally animals moved vertically and climbed over the barrier, or turned and navigated an edge of the obstacle, or completely reversed run direction. The avoidance strategies chosen depended on the size and configuration of the obstacle. Tests for the use of vision in detecting obstacles showed that its role, if any, is small. However, all manipulations that altered the antennal system changed behavior in a way consistent with the hypothesis that antennal mechanosensation plays a major role in collision avoidance. For example, reducing antennal length, or severing the main antennal nerve without altering the length produced significant increases in the frequency of collisions. Tests with tethered insects showed that (1) the antennae are preferentially directed forward as animals run, and (2) nearly simultaneous contact with both antennae is required to make the cockroach stop. Our data indicate that running cockroaches employ strategies that set their sensorimotor systems in a mode of readiness to deal with obstacles and they suggest that sensory information about the presence and configuration of obstacles is used to make choices, at very short latencies, about how to respond to obstructions.

Sexual dimorphism in shape and distribution of GABA-like immuno-reactive neurons in cricket terminal abdominal ganglion.

We studied age-related sexual dimorphism of the terminal abdominal ganglion in the cricket, Gryllus bimaculatus using osmium/ethyl-gallate staining and GABA immunohistochemistry. We determinedthat the volume of the terminal abdominal ganglion increases with increasing body size. The growth ratio between longitude and width in the terminal abdominal ganglion is the same in all nymph stages and sexes. However, the longitudinal growth of the male terminal abdominal ganglion ceases in the 8th instar and the adult stage. Therefore, in the adult stage, sexual dimorphism is observed in ganglion morphology. Additionally, sexual dimorphism is also observed in numbers of neuronal somata and GABA-like immunoreactive neurons in the terminal abdominal ganglion. At the beginning of the 8th instar, the number of somata is greater in female crickets than in males. GABA-like immunoreactive neurons, which were classified into eight clusters, increased between the 8th instar and adult in both sexes, but their numbers were sexually dimorphic in the 7th and 8th instars, and in the adult. Females had a greater number of GABA-like immunoreactive neurons than males. These differences occurred mainly in the 8th neuromere cluster, as well as the anterior region of the 9-11th neuromeres.

Timp-3 deficiency impairs cognitive function in mice.

Extracellular matrix (ECM) degradation is performed primarily by matrix metalloproteinases (MMPs). MMPs have recently been shown to regulate synaptic activity in the hippocampus and to affect memory and learning. The tissue inhibitor of metalloproteinase (Timp) is an endogenous factor that controls MMP activity by binding to the catalytic site of MMPs. At present, four Timp isotypes have been reported (Timp-1 through Timp-4) with 35-50% amino-acid sequence homology. Timp-3 is a unique member of Timp proteins in that it is bound to the ECM. In this study, we used the passive avoidance test, active avoidance test, and water maze test to examine the cognitive function in Timp-3 knockout (KO) mice. Habituation was evaluated using the open-field test. The water maze test showed that Timp-3 KO mice exhibit deterioration in cognitive function compared with wild-type (WT) mice. The open-field test showed decreased habituation of Timp-3 KO mice. Immunostaining of brain slices revealed the expression of Timp-3 in the hippocampus. In situ zymography of the hippocampus showed increased gelatinolytic activity in Timp-3 KO mice compared with WT mice. These results present the first evidence of Timp-3 involvement in cognitive function and hippocampal MMP activity in mice. Moreover, our findings suggest a novel therapeutic target to be explored for improvement of cognitive function in humans.

Factors associated with changes of care needs level in disabled older adults receiving home medical care: Prospective observational study by Osaka Home Care Registry (OHCARE).

AIM: To clarify factors associated with changes in care needs level and mortality among disabled older people receiving home medical care over a period of 2.5 years. METHODS: The study included 179 participants, aged ≥65 years, receiving home medical care, who consented to join the Osaka Home Care Registry study. The main outcome was changes in the care needs level of participants eligible for the long-term care insurance system. We investigated the association of changes in care needs level with basic characteristics and care-receiving status. RESULTS: At the 2.5-year follow up, 20.0% of participants showed deteriorated levels, and 41.8% of participants died. In multiple logistic regression, age (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.00-1.21; P = 0.051) and bone joint diseases (OR 0.34, CI 0.09-1.22; P = 0.098) were possible risks associated with deterioration of the care needs level. Male sex (OR 3.28, CI 0.91-11.74; P = 0.068) was a possible risk factor for mortality, and lower serum albumin (OR 0.22, CI 0.07-0.73) was a significant risk factor for mortality. CONCLUSIONS: We clarified the different factors associated with deterioration of the care needs level and mortality among disabled older people. Old age and bone joint diseases might be predictive factors for the further deterioration of independence of physical activity, and a low serum albumin level is considered to be strongly associated with increased mortality. Geriatr Gerontol Int 2019; 19: 1198-1205.

Akt activation prevents Apop-1-induced death of cells.

Apop-1 is a novel protein identified in cultured atherosclerotic smooth muscle cells of ApoE-deficient mice, and the expression of the Apop-1 protein induces the death of cultured cells. Insulin-like growth factor-1 (IGF-1) is a well-characterized survival factor for VSMC; however, the interaction between Apop-1 and survival factor IGF-1 in the mediation of cell death is poorly understood. In this report, we show that the IGF-1 signaling cascade protects VSMC against Apop-1-induced death. Furthermore, our data indicate that the inhibition of Apop-1-induced death by IGF-1 is mediated by the activation of the PI3K/Akt signaling pathway.

Ubiquitin carboxyl-terminal hydrolase L1, a novel deubiquitinating enzyme in the vasculature, attenuates NF-kappaB activation.

OBJECTIVE: We identified a ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene, which encodes a deubiquitinating enzyme and is expressed in the vasculature, by functional screening of a human endothelial cell (EC) cDNA library. UCHL1 is expressed in neurons, and abnormalities in UCHL1 are responsible for inherited Parkinson's disease via its effects on the ubiquitin-proteasome system. Therefore, the goal of present study was to clarify the role of the UCHL1 gene in vascular remodeling by evaluating nuclear factor-kappaB (NF-kappaB) inactivation in ECs and vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: From Northern blot and immunohistochemical analysis, the UCHL1 gene was endogenously expressed in vascular ECs, VSMCs, and brain tissue. Expression of UCHL1 was markedly increased in the neointima of the balloon-injured carotid artery and was also present in atherosclerotic lesions from human carotid arteries. Overexpression of the UCHL1 gene significantly attenuated tumor necrosis factor (TNF)-alpha-induced NF-kappaB activity in vascular cells and increased inhibitor of kappa B-alpha (IkappaB-alpha), possibly through the attenuation of IkappaB-alpha ubiquitination, leading to decreased neointima in the balloon-injured artery. In contrast, knockdown of UCHL1 by small interfering RNA resulted in increased NF-kappaB activity in VSMCs. CONCLUSIONS: These data suggest that UCHL1 may partially attenuate vascular remodeling through inhibition of NF-kappaB activity.

Merkel Cells Activate Sensory Neural Pathways through Adrenergic Synapses.

Epithelial-neuronal signaling is essential for sensory encoding in touch, itch, and nociception; however, little is known about the release mechanisms and neurotransmitter receptors through which skin cells govern neuronal excitability. Merkel cells are mechanosensory epidermal cells that have long been proposed to activate neuronal afferents through chemical synaptic transmission. We employed a set of classical criteria for chemical neurotransmission as a framework to test this hypothesis. RNA sequencing of adult mouse Merkel cells demonstrated that they express presynaptic molecules and biosynthetic machinery for adrenergic transmission. Moreover, live-cell imaging directly demonstrated that Merkel cells mediate activity- and VMAT-dependent release of fluorescent catecholamine neurotransmitter analogs. Touch-evoked firing in Merkel-cell afferents was inhibited either by pre-synaptic silencing of SNARE-mediated vesicle release from Merkel cells or by neuronal deletion of ß2-adrenergic receptors. Together, these results identify both pre- and postsynaptic mechanisms through which Merkel cells excite mechanosensory afferents to encode gentle touch. VIDEO ABSTRACT.

Tissue inhibitor of metalloproteinase-3 deficiency inhibits blood pressure elevation and myocardial microvascular remodeling induced by chronic administration of Nomega-nitro-L-arginine methyl ester in mice.

Hypertension is a major risk factor for cardiovascular disease. Thus, prevention of hypertension and consequent organ damage is important for reducing its incidence. In the present study, we examined the involvement of tissue inhibitor of metalloproteinase-3 (Timp-3) in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension and accompanying vascular remodeling in mice. L-NAME was orally administered to wild-type (WT) and Timp-3 knockout (KO) mice for 6 weeks, blood pressure was monitored, and histological changes in myocardial arteries were examined. After L-NAME administration, blood pressure was lower in Timp-3 KO mice than in WT mice. The coronary arteries of WT and Timp-3 KO mice were similar after L-NAME treatment and showed no differences compared to untreated control mice. However, cardiac microvessels differed histologically between WT and Timp-3 KO mice. Vascular walls were less thickened in Timp-3 KO than in WT mice, and fibrotic changes were significantly reduced in Timp-3 KO mice. Moreover, the L-NAME-induced production of reactive oxygen species in cardiac microvessels was lower in Timp-3 KO than in WT mice. These results indicate that Timp-3 plays an important role in L-NAME-induced hypertension and myocardial vascular remodeling. Our findings suggest that Timp-3 may be a novel therapeutic target for the treatment of hypertension and consequent organ damage.

Touch Receptors Undergo Rapid Remodeling in Healthy Skin.

Sensory tissues exposed to the environment, such as skin, olfactory epithelia, and taste buds, continuously renew; therefore, peripheral neurons must have mechanisms to maintain appropriate innervation patterns. Although somatosensory neurons regenerate after injury, little is known about how these neurons cope with normal target organ changes. To elucidate neuronal plasticity in healthy skin, we analyzed the structure of Merkel-cell afferents, which are gentle touch receptors, during skin remodeling that accompanies mouse hair-follicle regeneration. The number of Merkel cells is reduced by 90% and axonal arbors are simplified during active hair growth. These structures rebound within just days. Computational modeling predicts that Merkel-cell changes are probabilistic, but myelinated branch stability depends on Merkel-cell inputs. Electrophysiology and behavior demonstrate that tactile responsiveness is less reliable during active growth than in resting skin. These results reveal that somatosensory neurons display structural plasticity at the cost of impairment in the reliability of encoding gentle touch.