Efficacy of autologous platelet-rich plasma gel in patients with hard-to-heal diabetic foot ulcers: a multicentre study in Japan.

OBJECTIVE: To evaluate the healing outcome of a platelet-rich plasma (PRP) gel prepared using TKKT01 (a wound care device to prepare the PRP gel) in patients with hard-to-heal diabetic foot ulcers (DFUs) and who showed an inadequate response to ≥4 weeks of standard of care (SoC). METHOD: This open-label, single-arm, multicentre study was conducted in 15 centres in Japan. Eligible patients received PRP gel treatment twice a week for eight weeks, followed by a final evaluation after the completion of week 8 (day 57). The primary endpoint was the percentage of patients who achieved ≥50% reduction in wound radius at the final evaluation (achievement criterion, ≥60% of patients). Secondary endpoints included: wound area and volume reduction rates; time to possible wound closure by secondary intention; time to possible wound closure using a relatively simple procedure (e.g., skin graft and suture); and safety at the final evaluation. RESULTS: A total of 54 patients were included in the full analysis set, with 47 patients included in the per protocol set; the primary endpoint was met in 38/47 (80.9%) (95% confidence interval: 66.7-90.9%) patients who achieved ≥50% wound radius reduction at the final evaluation. High rates of wound area (72.8%) and volume (92.7%) reduction were observed at the final evaluation. The median time to possible wound closure by secondary intention and by use of a relatively simple procedure was 57 and 43 days, respectively. Complete wound closure at the final evaluation was achieved in 27 (57.4%) patients. No safety concerns were raised. CONCLUSION: In this study, the efficacy and safety of PRP gel treatment with TKKT01 in patients with hard-to-heal DFUs in Japan were confirmed by our findings. DECLARATION OF INTEREST: This study was funded by Rohto Pharmaceutical Co., Ltd., Japan. NO has been paid a consulting fee by Rohto Pharmaceutical Co., Ltd. KH is the Chief Medical Officer of Rohto Pharmaceutical. Co., Ltd. The other authors have no conflict of interest to declare.

Primary results of the SAVAL randomized trial of a paclitaxel-eluting nitinol stent versus percutaneous transluminal angioplasty in infrapopliteal arteries.

BACKGROUND: Effective and durable options for infrapopliteal artery revascularization for patients with chronic limb-threatening ischemia (CLTI) are limited. METHODS: The SAVAL trial is a prospective, multicenter, randomized trial of patients with CLTI and infrapopliteal artery lesions with total lesion length ⩽ 140 mm, stenosis ⩾ 70%, and Rutherford category 4-5 assigned 2:1 to treatment with the SAVAL self-expandable paclitaxel drug-eluting stent (DES) or percutaneous transluminal angioplasty (PTA) with an uncoated balloon. The primary effectiveness endpoint was primary vessel patency (i.e., core lab-adjudicated duplex ultrasound-based flow at 12 months in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesion). The primary safety endpoint was the 12-month major adverse event (MAE)-free rate; MAEs were defined as a composite of above-ankle index limb amputation, major reintervention, and 30-day mortality. The endpoints were prespecified for superiority (effectiveness) and noninferiority (safety) at a one-sided significance level of 2.5%. RESULTS: A total of 201 patients were enrolled and randomly assigned to treatment (N = 130 DES, N = 71 PTA). Target lesion length was 68.1 ± 35.2 mm for the DES group and 68.7 ± 49.2 mm for the PTA group, and 31.0% and 27.6% of patients, respectively, had occlusions. The 12-month primary patency rates were 68.0% for the DES group and 76.0% for the PTA group (Psuperiority = 0.8552). The MAE-free rates were 91.6% and 95.3%, respectively (Pnoninferiority = 0.0433). CONCLUSION: The SAVAL trial did not show benefit related to effectiveness and safety with the nitinol DES compared with PTA in infrapopliteal artery lesions up to 140 mm in length. Continued innovation to provide optimal treatments for CLTI is needed. (ClinicalTrials.gov Identifier: NCT03551496).

Two stages of salvaging an extensively necrotic foot with chronic limb-threatening ischemia by arterialization of great saphenous vein and free latissimus dorsi musculocutaneous flap transfer for wound coverage with the arterialized vein as the recipient vessel: A case report.

Patients with chronic limb-threatening ischemia (CLTI) without other options for adequate arterial revascularization could undergo deep (or distal) venous arterialization for limb salvage. Additionally, patients with extensive foot wound with CLTI sometimes require free flap transfer for limb salvage. We herein report a case of successful reconstructive limb-salvage surgery for an extensively necrotic foot with CLTI, using a two-stage operation involving venous arterialization using foot-perforating veins and subsequent free flap transfer (with preservation of the arterialized vein). The patient was a 59-year-old man with CLTI. The patient's right foot had dry necrotic tissue after Lisfranc joint amputation. Only one straight-line to the posterior tibial artery was achieved after endovascular therapies (four times). At the first stage of surgery, an arterial-venous shunt bypass from the superficial femoral artery to the distal great saphenous vein (GSV) (near the foot-perforating vein) was created. Arterial blood supply reached the necrotic area via the foot venous circulation system. At the second stage of surgery, free latissimus dorsi musculocutaneous flap (8 × 27 cm) transfer with preservation of the arterialized vein was performed. The pedicle artery was anastomosed to the bypass graft (end-to-side). The pedicle vein was anastomosed to the proximal stump of the GSV (end-to-end). The flap and residual foot survived completely, at a one-year follow-up postoperatively. An indocyanine green bypass-through angiography revealed the angiosome through the venous arterialization bypass graft, which included the flap; entire forefoot; and partial regions of the midfoot and heel. This two-stage operation might be considered a useful option for limb-salvage and complete wound-healing in patients with severe non-healing wound with CLTI. The two methods could compensate and overcome the problems of either method: incomplete wound-healing after venous arterialization, and the absence of a recipient artery for free flap transfer.

Effectiveness of negative pressure wound therapy for the wound of ileostomy closure: a multicenter, phase II randomized controlled trial.

BACKGROUND: The American Society of Surgery and American Society for Surgical Infections issued guidelines for surgical site infections (SSIs) in December 2016. These guidelines recommend a purse-string suture (PSS) for stoma closure as it facilitates granulation and enables open wound drainage. This study investigated the effect of using negative pressure wound therapy (NPWT) along with standard PSS and aimed to determine the optimal period of NPWT use. METHODS: The patients were divided into three groups as follows: Group A, postoperative wound management alone with gauze exchange as the representative of conventional PSS; Group B, the performed management was similar to that of Group A plus NPWT for 1 week; and Group C, the performed management was similar to that of Group A plus NPWT for 2 weeks. Regarding objective measures, the wound reduction rate was the primary outcome, and the incidence of SSIs, length of hospital stay, and wound healing duration were the secondary outcomes. RESULTS: In total, 30 patients (male: 18, female: 12) were enrolled. The average age was 63 (range: 43-84) years. The wound reduction rate was significantly higher in Group B than in Group A on postoperative days (PODs) 7 (66.1 vs. 48.4%, p = 0.049) and 10 (78.6 vs. 58.2%, p = 0.011), whereas no significant difference was observed on POD 14. Compared with Group A, Group C (POD 7: 65.9%, POD 10: 69.2%) showed an increase in the wound reduction rate on POD 7, although the difference was not significant (p = 0.075). SSIs were observed in Groups B (n = 2) and C (n = 2) (20%) but not in Group A (0%). CONCLUSIONS: The most effective duration of NPWT use for ileostomy closure with PSS in terms of the maximum wound reduction rate was from PODs 3 to 10. However, NPWT did not shorten the wound healing duration. NPWT may reduce the wound size but should be used with precautions for SSIs. The small sample size (30 cases), the use of only one type of NPWT system, and the fact that wound assessment was subjective and not blinded were the limitations of this study. Further studies are needed to confirm our findings. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000032174 (10/04/2018).

Hard-to-heal wound treatment medical devices: clinical trial protocol in Japan.

In consultation with academia and the Pharmaceuticals and Medical Devices Agency (PMDA), we have developed guidance for drafting protocols for clinical trials concerning medical devices for the healing of hard-to-heal wounds without ischaemia. The guidance summarises the validity of single-arm trials for hard-to-heal wounds, the definition of hard-to-heal wounds without ischaemia, methods of patient enrolment and clinical endpoints. This review focuses on the logical thinking process that was used when establishing the guidance for improving the efficiency of clinical trials concerning medical devices for hard-to-heal wounds. We particularly focused on the feasibility of conducting single-arm trials and also tried to clarify the definition of hard-to-heal wounds. If the feasibility of randomised control trials is low, conducting single-arm trials should be considered for the benefit of patients. In addition, hard-to-heal wounds were defined as meeting the following two conditions: wounds with a wound area reduction <50% at four weeks despite appropriate standards of care; and wounds which cannot be closed by a relatively simple procedure (for example, suture, skin graft and small flaps). Medical devices for hard-to-heal wound healing are classified into two types: (1) devices for promoting re-epithelialisation; and (2) devices for improving the wound bed. For medical devices for promoting re-epithelialisation, we suggest setting complete wound closure, percent wound area reduction or distance moved by the wound edge as the primary endpoint in single-arm trials for hard-to-heal wounds. For medical devices for improving the wound bed, we suggest setting the period in which wounds can be closed by secondary intention or a simple procedure, such as the primary endpoint.

High body mass index is a strong predictor of intraoperative acquired pressure injury in spinal surgery patients when prophylactic film dressings are applied: A retrospective analysis prior to the BOSS Trial.

We reported the efficacy of soft silicone multilayered foam dressings in preventing intraoperatively acquired pressure injuries (IAPIs) in the prone position using a Relton-Hall frame (BOSS trial). The aim of this study was to clarify the incidence and extract the risk factors for IAPIs in cases in which polyurethane film dressing was used against IAPIs before the BOSS trial period. This study conducted as a retrospective dual-center cohort study between August 2014 and Jun 2015 using the medical records in the operating room. The incidence of IAPIs that developed within 24 hours after surgery was 7.1% (7/99). The multivariate logistic regression analysis revealed that body mass index (BMI) (P = .0016, odds ratio [OR]: 1.22, 95% confidence interval (CI) 1.08-1.4) and length of surgery (P < .0001, OR 2.47, 95% CI 1.86-3.51) were independently associated with the development of IAPIs. Since high BMI was not extracted in BOSS trial, we conclude that the application of soft silicone multilayer foam dressings is important for preventing the development of IAPIs in patients with high BMI values.

Negative pressure wound therapy with instillation: International consensus guidelines update.

The use of negative pressure wound therapy with instillation and dwell time (NPWTi-d) has gained wider adoption and interest due in part to the increasing complexity of wounds and patient conditions. Best practices for the use of NPWTi-d have shifted in recent years based on a growing body of evidence and expanded worldwide experience with the technology. To better guide the use of NPWTi-d with all dressing and setting configurations, as well as solutions, there is a need to publish updated international consensus guidelines, which were last produced over 6 years ago. An international, multidisciplinary expert panel of clinicians was convened on 22 to 23 February 2019, to assist in developing current recommendations for best practices of the use of NPWTi-d. Principal aims of the meeting were to update recommendations based on panel members' experience and published results regarding topics such as appropriate application settings, topical wound solution selection, and wound and patient characteristics for the use of NPWTi-d with various dressing types. The final consensus recommendations were derived based on greater than 80% agreement among the panellists. The guidelines in this publication represent further refinement of the recommended parameters originally established for the use of NPWTi-d. The authors thank Karen Beach and Ricardo Martinez for their assistance with manuscript preparation.

An international consensus on device-related pressure ulcers: SECURE prevention.

Catherine Milne and colleagues present the findings of their review, ccna2@juno.com.

Branched xenopericardial roll graft replacement of an infected aortic arch graft.

Which graft material is the optimal graft material for the treatment of aortic graft infections is still a matter of controversy. We used a branched xenopericardial roll graft to replace an infected aortic arch graft as a "rescue" operation. The patient is alive and well 37 months postoperatively without recurrence of the infection and any surgical complication. This procedure may have the possibility to serve as an option for the treatment of aortic arch graft infection.

Convolutional neural networks for wound detection: the role of artificial intelligence in wound care.

OBJECTIVE: Telemedicine is an essential support system for clinical settings outside the hospital. Recently, the importance of the model for assessment of telemedicine (MAST) has been emphasised. The development of an eHealth-supported wound assessment system using artificial intelligence is awaited. This study explored whether or not wound segmentation of a diabetic foot ulcer (DFU) and a venous leg ulcer (VLU) by a convolutional neural network (CNN) was possible after being educated using sacral pressure ulcer (PU) data sets, and which CNN architecture was superior at segmentation. METHODS: CNNs with different algorithms and architectures were prepared. The four architectures were SegNet, LinkNet, U-Net and U-Net with the VGG16 Encoder Pre-Trained on ImageNet (Unet_VGG16). Each CNN learned the supervised data of sacral pressure ulcers (PUs). RESULTS: Among the four architectures, the best results were obtained with U-Net. U-Net demonstrated the second-highest accuracy in terms of the area under the curve (0.997) and a high specificity (0.943) and sensitivity (0.993), with the highest values obtained with Unet_VGG16. U-Net was also considered to be the most practical architecture and superior to the others in that the segmentation speed was faster than that of Unet_VGG16. CONCLUSION: The U-Net CNN constructed using appropriately supervised data was capable of segmentation with high accuracy. These findings suggest that eHealth wound assessment using CNNs will be of practical use in the future.

Design Strategies for Global Clinical Trials of Endovascular Devices for Critical Limb Ischemia (CLI)　- A Joint USA-Japanese Perspective.

For more than 10 years, the Harmonization by Doing (HBD) program, a joint effort by members from academia, industry and regulators from the United States of America (USA) and Japan, has been working to increase timely regulatory approval for cardiovascular devices through the development of practical global clinical trial paradigms. Consistent with this mission and in recognition of the increasing global public health effects of critical limb ischemia (CLI), academic and government experts from the USA and Japan have developed a basic framework of global clinical trials for endovascular devices for CLI. Despite differences in medical and regulatory environments and complex patient populations in both countries, we developed a pathway for the effective design and conduct of global CLI device studies by utilizing common study design elements such as patients' characteristics and study endpoints, and minimizing the effect of important clinical differences. Some of the key recommendations for conducting global CLI device studies are: including patients on dialysis; using a composite primary endpoint for effectiveness that includes 6-month post-procedure therapeutic success and target vessel patency; and using a 30-day primary safety endpoint of perioperative death and major adverse limb events. The proposed approach will be uniquely beneficial in facilitating both the initiation and interpretation of CLI studies and accelerating worldwide CLI device development and innovation.

The Japanese registry for surgery of ischial pressure ulcers: STANDARDS-I.

OBJECTIVE: To clarify the surgical indications and the appropriate perioperative management of ischial pressure ulcers (PUs). METHOD: A two-year prospective, nationwide registry study was carried out across 26 medical institutions in Japan. All participating institutions managed ischial PUs according to the standardisation of total management and surgical application for the refractory decubitus (STANDARDS-I) perioperative protocol. Analysis was conducted on a range of clinically or statistically important variables for the achievement of primary or secondary endpoints: complete wound healing and hospital discharge at three months, and complete wound healing at one month after surgery, respectively. RESULTS: A total of 59 patients took part in the study. All patients underwent surgery for ischial PUs during the study period. Patients who had achieved the primary endpoint had a higer preoperative functional independence measurement (FIM score), a higher 'G' score in the DESIGN-R scale and were more likely to have healed by primary intention. Patients who had achieved the secondary endpoint were more likely to have spastic paralysis, preoperative physiotherapy and localised infection of the wound, among other variables. CONCLUSION: This survey suggests that preoperative physiotherapy increases the speed of wound healing, and good granulation of the wound bed preoperatively increases the likelihood of woundless discharge from hospital, whereas the existence of comorbidities negatively influences the likelihood of woundless discharge from hospital. The study also suggests that the existence of spastic paralysis, preoperative infection of the wound, or surgical reduction of the ischial tubercle speeds up the healing of the wound. However, the wound failed to heal significantly more often in patients with increasing white blood cell count after surgery.

Soft silicone foam dressing is more effective than polyurethane film dressing for preventing intraoperatively acquired pressure ulcers in spinal surgery patients: the Border Operating room Spinal Surgery (BOSS) trial in Japan.

Preventing intraoperatively acquired pressure ulcers (IAPUs) in patients undergoing spinal surgery in the prone position using a Relton-Hall frame is challenging. We investigated the efficacy of soft silicone foam dressings in preventing IAPUs. A prospective dual-center sham study was conducted among patients undergoing elective spinal surgery in a general hospital and a university hospital in Japan. The incidence of IAPUs that developed when soft silicone foam dressings and polyurethane film dressings were used was compared on two sides in the same patient. IAPUs developed on the chest in 11 of 100 patients (11%). Polyurethane film dressings were associated with a significantly higher rate of IAPUs than soft silicone foam dressings (11 versus 3, P = 0·027). A multivariate logistic regression analysis revealed that a diastolic blood pressure of <50 mmHg (P = 0·025, OR 3·74, 95% confidence interval [CI] 1·18-13·08) and the length of surgery (by 1 hour: P = 0·038, OR 1·61, 95% CI 1·03-2·64) were independently associated with the development of IAPUs. The use of soft silicone foam dressings reduced the risk of IAPUs (P = 0·019, OR 0·23, 95% CI 0·05-0·79) and was more effective than film dressings for preventing IAPUs in spinal surgery patients.

Presepsin as a predictor of critical colonization in CLI hemodialysis patients.

Infection during critical limb ischemia (CLI) is a challenging issue. Plasma presepsin is a novel biomarker for infection, which is related to bacterial phagocytosis by macrophages. The purpose of this study was to investigate the validity of presepsin as an indicator and predictor for early detection of infectious CLI. A retrospective observational study was conducted among 20 CLI patients (Rutherford 5 and 6) on hemodialysis (HD). Twenty CLI patients on HD (mean age 70.7 ± 5.6 years, male 85%) and 15 healthy patients on HD without CLI and infection (control group) were analyzed. All CLI patients received appropriate revascularization and plastic surgical treatment. CLI patients were classified into two groups: the healing group with complete epithelialization without discharge and the nonhealing group with infection signs. Plasma presepsin was measured and compared among the two groups and the control group using an automated immunoanalyzer, PATHFAST, based on a noncompetitive chemiluminescent enzyme immunoassay. The median plasma presepsin and its interquartile range were 1,320 (1,055-1,465) pg/mL in the control group, 1,320 (1,050-1,613) pg/mL in the healing group and 3,193 (2,519-3,832) pg/mL in the nonhealing group. The plasma presepsin concentrations were significantly higher in the nonhealing group compared with the control group (p < 0.001) and the healing group (p < 0.01). A receiver operating characteristic curve analysis revealed that presepsin had highest accuracy (0.979) among various inflammatory markers, including C-reactive protein and the white blood cell count. The diagnostic cutoff value of 2,083 pg/mL was able to distinguish the nonhealing group and healing group with a sensitivity of 100% and a specificity of 88.9%. Our results suggest that plasma presepsin may be useful for predicting "critical colonization" and "infection" in nonhealing CLI in HD patients, therefore, the definitive cutoff value may be used for determinating the indication for reintervention and/or major limb amputation.

Comparison of Nasal Septum and Ear Cartilage as a Graft for Lower Eyelid Reconstruction.

In lower eyelid reconstruction, several types of grafts from the nasal septum, ear cartilage, buccal mucosa, and hard palate mucosa have been used for an inner layer of the lower eyelid, but there have been no studies comparing these grafts. The authors retrospectively reviewed our cases of lower eyelid reconstruction, and compared chondromucosal grafts from the nasal septum (N = 8) and ear cartilage grafts (N = 10) for an inner layer of the lower eyelid. The authors observed no significant difference in operative time, blood loss, or length of hospital stay between the "nasal septum" and "ear cartilage" groups. The final results were aesthetically and functionally satisfactory in both groups. In the nasal septum group, 1 patient suffered from perforation of the nasal septum and another patient suffered from nasal bleeding postoperatively. There were no donor site complications in the ear cartilage group. These findings indicate that both a chondromucosal graft from the nasal septum and an ear cartilage graft are good grafts for an inner layer of the lower eyelid. Regarding the donor site, however, an ear cartilage graft has the advantage of a lower complication rate.

Examination of tissue oxygen saturation (StO2) changes associated with vascular pedicle occlusion in a rat Island flap model using near-Infrared spectroscopy.

PURPOSE: The purpose of this study was to perform continuous StO(2) monitoring of rat island flaps during pedicle vessel occlusion using near-infrared spectroscopy (NIRS) in order to collect experimental data for StO(2) flap monitoring under optimized conditions. MATERIALS AND METHODS: Twenty rats were used in this study. The 3 × 3 cm(2) epigastric skin island flaps were elevated on either side. The animals were randomly assigned to two groups; an arterial occlusion group (n = 10) and a venous occlusion group (n = 10). The StO(2) values of the flaps were observed for over 30 min for the pedicle artery or venous occlusion, followed by an additional 30 min release. RESULTS: The baseline StO(2) value was 78.4% ± 3.2% in the arterial occlusion group, compared to 78.5% ± 5.8% in the venous occlusion group, with no significant differences (P > 0.05). The StO(2) values decreased immediately after arterial occlusion, whereas a temporal StO(2) increase was initially observed after venous occlusion, followed by a StO(2) decrease. The StO(2) values decreased 27.3% ± 7.1% after arterial occlusion and 28.4% ± 19.1% after venous occlusion at 30 min after pedicle vessel clamping (P > 0.05). The StO(2) values were 0.4% ± 5.8% lower than baseline 30 min after arterial release (P > 0.05), while 18.9% ± 11.3% lower than baseline 30 min after venous release (P < 0.01). CONCLUSION: NIRS can be used to indicate StO(2) changes in flaps with the pedicle vessel occlusion and differentiate between pedicle artery and vein occlusion. Further investigations are needed to obtain definitive evidence associated with predicting the degree of flap viability and determine the practical use of this technique.

Poor short-term outcomes for prognostic high-risk patients with chronic limb-threatening ischemia undergoing endovascular therapy.

BACKGROUND: The prognosis of chronic limb-threatening ischemia (CLTI) is poor, with an expected life expectancy of 2 or more years, which significantly influences treatment decisions. However, death may occur at the early stages of treatment for wound healing, and aggressive treatment may limit the quality of life of such patients. In patients with CLTI undergoing endovascular therapy (EVT), the Wound, Ischemia, and foot Infection (WIfI) clinical stage, male sex, older age, non-ambulatory status, low body mass index, and dialysis have been reported as predictors of mortality risk. However, most studies have not fully investigated the WIFI clinical stage as a prognostic predictor of CLTI. This study aimed to evaluate short-term prognosis and wound healing rates using the prognostic predictors (PPs) indicated above in risk-stratified patients with CLTI who underwent EVT. METHODS: This retrospective single-center observational study included 61 CLTI patients undergoing EVT from April 2020 to October 2022. The patients were divided into a high-risk group (PPs ≥ 4, n = 20) and low-risk group (PPs ≤ 3, n = 41) according to the number of PPs. Survival and wound healing rates within one year were compared between these two groups. RESULTS: The mean age of the patients was 74.7 ± 1.6 years, and 42 (68.9%) were male. Among these patients, the high-risk group compared with the low-risk group had a significantly worse survival rate within one year (46.4% vs. 84.7%, log-rank p < 0.001). Fifteen patients died within one year. Of these, seven deaths were cardiovascular deaths and six were deaths from infectious diseases. Cox proportional hazards analysis showed that WIfI clinical stage 4 (p = 0.043, hazard ratio [HR] = 4.85) and the male sex (p = 0.037, HR = 6.34) influenced the prognosis of this population. The high-risk group tended to have a worse wound healing rate within one year than that had by the low-risk group (55.4% vs. 83.0%, log-rank p = 0.086). CONCLUSIONS: The assessment of short-term prognosis and wound healing rates using PPs may be useful. Discussing the results of short-term clinical outcome assessments with patients should be considered when determining their individualized treatment plans.

Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice.

The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel, expressed on endothelial cells and encoded by P2rx4 in mice, has a key role in the response of endothelial cells to changes in blood flow. P2rx4(-/-) mice do not have normal endothelial cell responses to flow, such as influx of Ca(2+) and subsequent production of the potent vasodilator nitric oxide (NO). Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2rx4(-/-) mice. Furthermore, P2rx4(-/-) mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wild-type mice. Moreover, no adaptive vascular remodeling, that is, a decrease in vessel size in response to a chronic decrease in blood flow, was observed in P2rx4(-/-) mice. Thus, endothelial P2X4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling.