A human brain vascular atlas reveals diverse mediators of Alzheimer's risk.

The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.

Physiological blood-brain transport is impaired with age by a shift in transcytosis.

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

Stem cells from trabecular meshwork cells can secrete extracellular matrix.

Isolation of trabecular meshwork stem cells in vitro provides the foundation of a novel treatment for glaucoma. Trabecular meshwork stem cells (TMSCs) of the fetal calve were extracted and cultured for this experiment. TMSCs were isolated through side population cell sorting. TMSCs were then identified using immunofluorescent staining. Extracellular matrix (ECM) expression in TM cells derived from TMSCs was evaluated with Western blot. Our results showed a positive expression of stem cell markers Notch1 and OCT-3/4 in TMSCs, but no TM cells markers TIMP3 or AQP1. In contrast, primary TM cells expressed these TM cell markers but no stem cell markers. Our result confirmed that there are expression of ECM components, such as fibronectin, laminin, collagen I and collagen IV in TM cells differentiated from TMSCs. CONCLUSION: TM cells derived from TMSCs can secrete ECM components which is important for sustain the physiological function.

Synergistic health effects of air pollution, temperature, and pollen exposure: a systematic review of epidemiological evidence.

BACKGROUND: Exposure to heat, air pollution, and pollen are associated with health outcomes, including cardiovascular and respiratory disease. Studies assessing the health impacts of climate change have considered increased exposure to these risk factors separately, though they may be increasing simultaneously for some populations and may act synergistically on health. Our objective is to systematically review epidemiological evidence for interactive effects of multiple exposures to heat, air pollution, and pollen on human health. METHODS: We systematically searched electronic literature databases (last search, April 29, 2019) for studies reporting quantitative measurements of associations between at least two of the exposures and mortality from any cause and cardiovascular and respiratory morbidity and mortality specifically. Following the Navigation Guide systematic review methodology, we evaluated the risk of bias of individual studies and the overall quality and strength of evidence. RESULTS: We found 56 studies that met the inclusion criteria. Of these, six measured air pollution, heat, and pollen; 39 measured air pollution and heat; 10 measured air pollution and pollen; and one measured heat and pollen. Nearly all studies were at risk of bias from exposure assessment error. However, consistent exposure-response across studies led us to conclude that there is overall moderate quality and sufficient evidence for synergistic effects of heat and air pollution. We concluded that there is overall low quality and limited evidence for synergistic effects from simultaneous exposure to (1) air pollution, pollen, and heat; and (2) air pollution and pollen. With only one study, we were unable to assess the evidence for synergistic effects of heat and pollen. CONCLUSIONS: If synergistic effects between heat and air pollution are confirmed with additional research, the health impacts from climate change-driven increases in air pollution and heat exposure may be larger than previously estimated in studies that consider these risk factors individually.

Successful Management of Anti-TNF-Induced Psoriasis Despite Continuation of Therapy in a Pyoderma Gangrenosum Patient

Pyoderma gangrenosum is an inflammatory, neutrophil-mediated disorder that is difficult to treat. Tumor necrosis factor and other inflammatory mediators are among the most promising therapeutic targets. We present a case of a 60-year-old woman with recalcitrant pyoderma gangrenosum treated with adalimumab, who paradoxically developed psoriasis. Secukinumab, an interleukin-17 inhibitor, was added to her regimen, resulting in successful treatment of her psoriasis. Secukinumab was later replaced by methotrexate, resulting in remission of both pyoderma gangrenosum and maintenance of a psoriasis-free state. We conclude that paradoxically induced psoriatic lesions can resolve with adjunct therapy despite continuation of anti-tumor necrosis factor agents. J Drugs Dermatol. 2020;19(2)199-201. doi:10.36849/JDD.2020.4662

Feasibility and Acceptability of a Remotely Delivered, Web-Based Behavioral Intervention for Men With Prostate Cancer: Four-Arm Randomized Controlled Pilot Trial.

BACKGROUND: Diet and exercise may be associated with quality of life and survival in men with prostate cancer. OBJECTIVE: This study aimed to determine the feasibility and acceptability of a remotely delivered web-based behavioral intervention among men with prostate cancer. METHODS: We conducted a multi-site 4-arm pilot randomized controlled trial of a 3-month intervention (TrueNTH Community of Wellness). Eligibility included self-reported prostate cancer diagnosis, having a personal device that connected to the internet, age ≥18 years, and ability to read English and receive text messages and emails. Men receiving chemotherapy or radiation, or those who reported contraindications to exercise, could participate with physician clearance. Participants were randomized (1:1:1:1) to additive intervention levels: website; website and personalized diet and exercise prescription; website, personalized prescription, Fitbit, and text messages; and website, personalized prescription, Fitbit, text messages, and 2 30-minute phone calls-one with an exercise trainer and one with a registered dietician. Primary outcomes were feasibility (accrual and attrition) and acceptability (survey data and website use). We described self-reported diet and exercise behavior at the time of enrollment, 3 months, and 6 months as secondary outcomes. RESULTS: In total, 202 men consented and were randomized between August 2017 and September 2018 (level 1: 49, level 2: 51, level 3: 50, level 4: 52). A total of 160 men completed the onboarding process and were exposed to their randomly assigned intervention (38, 38, 42, and 42 in levels 1, 2, 3, and 4, respectively). The follow-up rate was 82.7% (167/202) at 3 months and 77.2% (156/202) at 6 months. Participants had a median age of 70 years and were primarily White and college educated. Website visit frequency over the 3-month intervention period increased across levels (median: 2, 9, 11, and 16 visits for levels 1, 2, 3, and 4, respectively). Most were satisfied or very satisfied with the intervention (20/39, 51%; 27/42, 64%; 23/44, 52%; and 27/42, 64% for levels 1, 2, 3, and 4, respectively). The percentage of men who reported being very satisfied was highest among level 4 participants (10/42, 24% vs 4/39, 10%; 5/42, 12%; and 5/44, 11% for levels 1, 2, and 3, respectively). Dissatisfaction was highest in level 1 (5/39, 13% vs 1/42, 2%; 3/44, 7%; and 2/42, 5% for levels 2, 3, and 4, respectively). We observed small improvements in diet and physical activity at 3 months among men in level 4 versus those in level 1. CONCLUSIONS: A web-based, remotely delivered, tailored behavioral intervention for men with prostate cancer is feasible. Future studies are warranted to increase the effect of the intervention on patient behavior while maintaining sustainability and scalability as well as to design and implement interventions for more diverse populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT03406013; http://clinicaltrials.gov/ct2/show/NCT03406013.

Treatment of Primary Aldosteronism Reduces the Probability of Obstructive Sleep Apnea.

BACKGROUND: Aldosterone excess is hypothesized to worsen obstructive sleep apnea (OSA) symptoms by promoting peripharyngeal edema. However, the extent to which primary aldosteronism (PA), hypertension, and body mass index (BMI) influence OSA pathogenesis remains unclear. METHODS: We conducted a cross-sectional study of PA patients from our endocrine database to retrospectively evaluate OSA probability before and after adrenalectomy or medical management of PA. A control group of patients undergoing adrenalectomy for nonfunctioning benign adrenal masses was also evaluated. We categorized patients as high or low OSA probability after evaluation with the Berlin Questionnaire, a validated 10-question survey that explores sleep, fatigue, hypertension, and BMI. RESULTS: We interviewed 91 patients (83 PA patients and eight control patients). Median follow-up time was 2.6 y. The proportion of high OSA probability in all PA patients decreased from 64% to 35% after treatment for PA (mean Berlin score 1.64 versus 1.35, P < 0.001). This decline correlated with improvements in hypertension (P < 0.001) and fatigue symptoms (P = 0.03). Both surgical (n = 48; 1.69 versus 1.33, P < 0.001) and medical (n = 35; 1.57 versus 1.37, P = 0.03) treatment groups demonstrated reduced OSA probability. BMI remained unchanged after PA treatment (29.1 versus 28.6, P = nonsignificant), and the impact of treatment on OSA probability was independent of BMI. The control surgical group showed no change in OSA probability after adrenalectomy (1.25 versus 1.25, P = nonsignificant). CONCLUSIONS: Both surgical and medical treatments of PA reduce sleep apnea probability independent of BMI and are associated with improvements in hypertension and fatigue. Improved screening for PA could reduce OSA burden.

End stage scurvy in the developed world: A diagnostic conundrum but not to be mistaken for pyoderma gangrenosum.

Scurvy is a clinical syndrome, resulting from ascorbic acid deficiency. Prevalence of the condition is now extremely low in the Western population and its diagnosis can be challenging without a high index of suspicion. When cases do present, they are often misdiagnosed initially. Therefore, a thorough history, physical exam, and laboratory evaluation are key to showing this now rare but extremely well-known disease. We report a case of scurvy manifesting as persistent non-healing lower-extremity ulcerations, initially mistaken for pyoderma gangrenosum. The patient responded to appropriate replacement therapy, but ulcers were slow to heal. As was the case in our patient, symptom reversal may require additional nutritional replacement. We encourage physicians to consider nutritional deficiencies in their differential diagnoses and highlight the incidence of malnutrition in the proper clinical setting to avoid diagnostic delay.

Trends of genetic screening in patients with pheochromocytoma and paraganglioma: 15-year experience in a high-volume tertiary referral center.

BACKGROUND AND OBJECTIVES: Genetic testing for pheochromocytoma and paraganglioma allows for early detection of hereditary syndromes and enables close follow-up of high-risk patient. We investigated the trends in genetic testing among patients at a high-volume referral center and evaluated the prevalence of pheochromocytomas and paragangliomas. METHODS: We reviewed the charts of 129 patients who underwent adrenalectomy for pheochromocytoma and paraganglioma between January 2000 and July 2015. To evaluate for trends in genetic testing, patients were divided by year of diagnosis: 2000-2005 (group 1, n = 35), 2006-2010 (group 2, n = 44), and 2011-2015 (group 3, n = 50). RESULTS: Among 129 patients the mean age was 47 years and 56% were women. Groups 2 and 3 were more frequently referred for genetic consultation than group 1, 73%, and 94% versus 26% (P < 0.001). A total of 67% followed up on the referral. The prevalence of genetic mutation was 50% (21/42 tested). The percentage with a genetic syndrome was 23%, 28%, and 22% respectively for groups 1, 2, and 3. CONCLUSIONS: Referral for genetic counseling significantly increased in the past 15 years. However, only two-thirds of patients followed up with genetic counselors and, therefore, clinicians can do more to improve the adherence rate for genetic counseling.

Evaluating Screening Tests for Depression in Post-Stroke Older Adults.

BACKGROUND: Uncertainty surrounds which screening test to use in older patients with poststroke depression, in whom symptoms of depression are more complex and often occur in conjunction with other comorbidities. We evaluated screening tests for depression among a cohort of older ambulatory individuals with comorbid ischemic heart disease and prior stroke. METHODS: We administered 4 depression screening instruments to 148 participants with ischemic heart disease and self-reported stroke from The Heart and Soul Study. Instruments included the 10-item Center for Epidemiologic Studies Depression Scale (CES-D), 9-item and 2-item versions of the Patient Health Questionnaire (PHQ-9 and PHQ-2), and the Whooley questions, a 2-item yes/no questionnaire. We administered the computerized version of the National Institute of Mental Health Diagnostic Interview Schedule as a gold standard. RESULTS: Of the 148 participants, 35 (24%) had major depression. The Whooley questions demonstrated the highest sensitivity for detection (89%), followed by the CES-D (80%), PHQ-2 with cut point ≥2 (79%), PHQ-9 (51%), and PHQ-2 with cut point ≥3 (32%). The Whooley questions had a specificity of 0.66, a positive likelihood ratio of 2.61, and a negative likelihood ratio of 0.82. We observed no significant difference in the area under the receiver operating characteristic curve across the 4 instruments. CONCLUSION: In a cohort of ambulatory older adults with coronary heart disease and prior stroke, depression occurred in a fourth of the participants. The simple Whooley questions screening instrument can efficiently detect depression with a high sensitivity in this population, one representative of older patients commonly encountered within a primary care setting.

Transitional dialysis care units: A new approach to increase home dialysis modality uptake and patient outcomes.

Home hemodialysis (HHD) and peritoneal dialysis (PD) are associated with better clinical outcomes, lower hospitalization rates, and improved quality of life compared with conventional in-center hemodialysis. However, <12% of patients requiring dialysis therapy use HHD or PD in the United States, even though over 90% of nephrologists would choose home-based dialysis modalities for themselves. Inadequate patient education and decision-making support are key barriers to patients choosing home-based therapy. Likewise, there are key challenges for dialysis providers, including development and optimal delivery of education materials, appropriate staffing, and training. The Satellite Healthcare Optimal Transitions (OT) Program was developed to provide education and decision support to patients during the transitional period. OT provides in-depth education in all dialysis modalities at the start of dialysis over a flexible time period (1-4 weeks, adapted for various learning curves) to allow for time to physical stabilization, self-care training, and modality choice based on each patient's individual life motivations, goals, and environments. OT may provide value to patients and providers by providing comprehensive support for dialysis modality selection, resulting in increased patient confidence to execute home dialysis with the potential for improved patient outcomes, and reduced hospitalizations.

A rare presentation of congenital syphilis: Pemphigus syphiliticus in a newborn infant with extensive desquamation of the extremities.

Congenital syphilis is an infection transmitted from mother to fetus and can present with early but variable cutaneous manifestations. In rare situations, a bullous eruption known as pemphigus syphiliticus may develop. We present an unusual case of broad desquamation of the extremities in a newborn infant who was found to have congenital syphilis. Pemphigus syphiliticus should be considered in the differential diagnosis of neonatal bullous eruptions and erosions.

CD4+ virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.

It is widely accepted that central and effector memory CD4+ T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. Here we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts. CD4+ T cell repertoire analysis of highly purified T cell populations from naive animals revealed that the HEL-specific clones displayed effector and central "memory" cell surface phenotypes even prior to having encountered their cognate antigen. Furthermore, HEL-inexperienced CD4+ T cells were found to reside within the naïve, regulatory, central memory, and effector memory T cell populations at similar frequencies and the majority of the CD4+ T cells within the regulatory and memory populations were unexpanded. These findings support a new paradigm for CD4+ T cell maturation in which a specific clone can undergo a differentiation process to exhibit a "memory" or regulatory phenotype without having undergone a clonal expansion event. It also demonstrates that a foreign-specific T cell is just as likely to reside within the regulatory T cell compartment as it would the naïve compartment, arguing against the specificity of the regulatory T cell compartment being skewed towards self-reactive T cell clones. Finally, we demonstrate that the same set of foreign and autoreactive CD4+ T cell clones are repetitively generated throughout adulthood. The latter observation argues against T cell-depleting strategies or autologous stem cell transplantation as therapies for autoimmunity-as the immune system has the ability to regenerate pathogenic clones.

Severe pellagra masked by concurrent plaque psoriasis: a case report of a hidden diagnosis.

Despite characteristic features, psoriasis can mimic other dermatologic conditions, such as seborrheic dermatitis, lichen simplex chronicus, and certain nutritional deficiencies such as pellagra. We present a patient with a longstanding history of severe plaque psoriasis who presented with disfiguring scaly plaques involving greater than 80% body surface area. The patient's disease was minimally responsive to multiple therapies. Repeat punch biopsies demonstrated parakeratosis, psoriasiform hyperplasia, and dilated blood vessels consistent with psoriasis. Given atypical clinical features and overall poor treatment response additional work up was obtained. A serum nutritional panel was consistent with niacin deficiency and the patient later revealed extensive alcohol intake. A diagnosis of concurrent pellagra was made and the patient was started on niacin supplementation and instructed to reduce alcohol intake, while continuing adalimumab and high potency topical steroids. Within two weeks, his disease had markedly improved. Pellagra presents characteristically with a photosensitivity dermatitis that may appear clinically and histologically similar to psoriasis. It is important to maintain an index of suspicion for a secondary pathology in treatment-resistant psoriasis.

Physical Activity and Kidney Injury in Pediatric and Young Adult Kidney Transplant Recipients.

OBJECTIVES: To quantify physical activity and grip strength in pediatric kidney transplant recipients and describe attitudes about exercise and exercise counseling given concerns about allograft injury. STUDY DESIGN: This was a cross-sectional analysis of 101 kidney transplant recipients (7-21 years old) >6 months post-transplant. Patients completed the Physical Activity Questionnaire (PAQ). Grip strength was measured with a dynamometer. We asked about activity limitations and provider counseling. Univariate analysis and multiple linear regression were used to determine independent predictors of PAQ score and grip strength z score. RESULTS: We enrolled 101 of 122 eligible patients. Median PAQ score was 2.2 (range 0-5) and was lower compared with controls (P < .001). The average grip strength z score was -1.1 and -0.7 in the right and left hand, respectively. Predictors of lower grip strength were younger age (P = .036), non-African American race (P = .029), lower height z score (P = .010), and longer percentage of lifetime with kidney disease (P = .029). Although 49% and 67% limited exercise before and after transplant, respectively, 67% reported increased activity after transplant. By parent report, provider counseling included limiting certain activities (71%) and encouraging regular exercise (45%). CONCLUSION: Physical activity and grip strength are low after kidney transplant. Patients perceive an emphasis on exercise limitations rather than the benefits of regular exercise. Interventions that encourage physical activity may be beneficial.

Galactomannan antigen detection using bronchial wash and bronchoalveolar lavage in patients with hematologic malignancies.

BACKGROUND: The diagnosis of invasive pulmonary aspergillosis is challenging. It is unclear whether galactomannan (GM) results from bronchial wash (BW) and bronchoalveolar lavage (BAL) samples differ in a clinically meaningful way. RESULTS: Ninety-six paired (BAL and BW) samples from 85 patients were included. The average age was 53 years, 61 % of the patients were male, and 74.1 % had an underlying diagnosis of AML/MDS (ALL 7.1 %, other hematologic malignancy 18.8 %). 57 (67.1 %) patients were neutropenic, and 56 (65.9 %) patients were receiving mold-active drugs at least 48 h prior to bronchoscopy. The overall agreement between GM detection from BW and BAL was 63.5 % (K = 0.152; 95 % CI 0.008-0.311) and 73 % (K = 0.149; 95 % CI 0.048-0.348) at cut off ≥0.5 and ≥1.0, respectively. Among 43 positive samples, using a GM cut-off of 0.5, 39 (90.5 %) were positive in BW samples whereas 12 (29.3 %) were positive in BAL samples. The median level of GM in BW (0.28) samples was significantly higher than in BAL (0.20) samples among 53 samples with negative results (P = 0.001). There was no statistically significant difference in the median GM values between the BW and BAL samples with positive results (P = 0.08). There was no significant difference in GM detection between samples with positive and negative results with regard to antifungal, beta lactam antibacterial treatment or neutropenia (60.5 vs 56.6 %; 53.9 vs 46 %; 65.1 vs 54.7 %, respectively). CONCLUSION: This retrospective study examining two collection techniques suggests that BW may have higher diagnostic yield compared to bronchoalveolar lavage for GM detection.

Evaluation of URO17® to improve non-invasive detection of bladder cancer.

BACKGROUND: The gold standard for detecting bladder cancer is cystoscopy with biopsy or transurethral resection confirming histologic diagnosis. URO17® employs a chromogenically labeled monoclonal antibody to keratin 17 (k17), an intermediate filament cytoskeleton molecule associated with bladder, pancreatic, and cervical cancers. Preliminary studies evaluating k17 demonstrated a high sensitivity and specificity for the detection of bladder cancer, supporting the need for further study. OBJECTIVE: To evaluate the sensitivity and specificity of URO17. METHODS: This is a cross-sectional study of participants undergoing urologic procedures between July 6, 2018 and July 17, 2019 at a single institution. Patients undergoing cystectomy, endoscopic bladder and/or upper tract procedure for probable urothelial carcinoma comprised cases; patients undergoing urologic procedures for other reasons comprised the control group (i.e. prostatectomy, nephrectomy, etc.). Voided urine samples were at the time of procedure; a minority of participants underwent multiple resections in the study period, thus, as many as three urine samples were taken from any given participant. Samples were distributed for blinded testing with URO17. Sensitivity and specificity were calculated. RESULTS: In 152 participants and 167 samples, URO17 demonstrated an overall sensitivity of 90% and 92% and a specificity of 88% and 87%, respectively. In 76 participants and 91 samples from patients with suspected urothelial carcinoma, the sensitivity was 90% and 92%, and the specificity was 50% and 54%, respectively. No controls demonstrated a positive URO17 result, and URO17 superseded urine cytology detection of low-grade and high-grade Ta. False positive results were associated with inflamed tissue or urothelial atypia on histology; the large majority had a history of intravesical therapy. CONCLUSION: Limitations include cross-sectional design and convenience sampling. URO17 may improve sensitivity of urine cytology in the detection of urothelial cancer, though further study is required to refine the application of this biomarker in clinical practice.

Sodium tanshinone IIA sulfonate inhibits canonical transient receptor potential expression in pulmonary arterial smooth muscle from pulmonary hypertensive rats.

Danshen, the dried root of Salvia miltiorrhiza, is widely used in clinics in China for treating various diseases, including cardiovascular diseases. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA isolated as the major active component from Danshen, was recently reported to be effective in attenuating the characteristic pulmonary vascular changes associated with chronically hypoxic pulmonary hypertension (CHPH); however, the underlying detailed mechanisms are poorly understood. In this study, we investigated the effects of STS on basal intracellular Ca(2+) concentration ([Ca(2+)](i)) and store-operated Ca(2+) entry (SOCE) in distal pulmonary arterial smooth muscle cells (PASMCs) exposed to prolonged hypoxia or isolated from CHPH rats. SOCE measured by Mn(2+) quenching of Fura-2 fluorescence in PASMCs from rats exposed to chronic hypoxia (10% O(2), 21 d) was increased by 59%, and basal [Ca(2+)](i) was increased by 119%; this effect was inhibited by intraperitoneal injection of STS. These inhibitory effects of STS on hypoxic increases of SOCE and basal [Ca(2+)](i) were associated with reduced expression of canonical transient receptor potential (TRPC)1 and TRPC6 in distal pulmonary arterial smooth muscle and decreases on right ventricular pressure, right ventricular hypertrophy, and peripheral pulmonary vessel thickening. In ex vivo cultured distal PASMCs from normoxic rats, STS (0-25 µM) dose-dependently inhibited hypoxia-induced cell proliferation and migration, paralleled with attenuation in increases of basal [Ca(2+)](i), SOCE, mRNA, and protein expression of TRPC1 and TRPC6. STS also relieved right ventricular systolic pressure, right ventricular hypertrophy, and TRPC1 and TRPC6 protein expression in distal pulmonary arteries in a monocrotaline-induced rat model of pulmonary arterial hypertension. These results indicate that STS prevents pulmonary arterial hypertension development likely by inhibiting TRPC1 and TRPC6 expression, resulting in normalized basal [Ca(2+)](i) and attenuated proliferation and migration of PASMCs.