What does one mean by "arterial blood oxygenation?"

We used the following question in a large classroom session attended by undergraduate medical students and doctors with a Bachelor of Medicine and Bachelor of Surgery (MBBS) degree (240 in all) to test for conceptual understanding as to what constitutes arterial blood oxygenation. The question read as follows: Which one of the following physiological parameters taken alone tells you that arterial blood oxygenation in a critically ill patient is satisfactory? A. (Alveolar-arterial) O(2) gradient=10 mmHg. B. Partial pressure of O(2) in arterial blood=95 mmHg. C. O(2)saturation of hemoglobin>90%. D. Blood hemoglobin concentration=12 g/dl. Only 25 of 240 students correctly indicated that none of the above parameters taken alone could give us this information. Once students turned in their answers, we presented five examples illustrating how none of the above answers could be used alone to assess arterial blood oxygenation. Students were then asked to provide written feedback on their understanding of this topic. The majority of students indicated that they were satisfied that they got rid of a misconception.     

Is there a haemodynamic advantage associated with cuffed arterial anastomoses?

The development of intimal hyperplasia at arterial bypass graft anastomoses is a major factor responsible for graft failure. A revised surgical technique, involving the incorporation of a small section of vein (vein cuff) into the distal anastomosis of PTFE grafts, results in an altered distribution of intimal hyperplasia and improved graft patency rates, especially for below-knee grafts. Numerical simulations have been conducted under physiological conditions to identify the flow behaviour in a typical cuffed bypass model and to determine whether the improved performance of the cuffed system can be accounted for by haemodynamic factors. The flow patterns at the cuffed anastomosis are significantly different to those at the conventional end-to-side anastomosis. In the former case, the flow is characterised by an expansive, low momentum recirculation within the cuff. Separation occurs at the graft heel, and at the cuff toe as the blood enters the recipient artery. Wall shear stresses in the vicinity of the cuff heel are low, but high shear stresses and large spatial gradients in the shearing force act on the artery floor during systole. In contrast, a less disturbed flow prevails and the floor shear stress distribution is less adverse in the conventional model. In conclusion, aspects of the anastomotic haemodynamics are worsened when the cuff is employed. The benefits associated with the cuffed grafts may be related primarily to the presence of venous material at the anastomosis. Therefore, caution is advised with regard to the use of PTFE grafts, pre-shaped to resemble a cuffed geometry.     

Physiologically based pharmacokinetic modeling of arterial – antecubital vein concentration difference

Background  

Modeling of pharmacokinetic parameters and pharmacodynamic actions requires knowledge of the arterial blood concentration. In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration.     

Histological study on the arterial wall of G?ttingen miniature swine

In order to clarify the histological aspects of arterial walls of miniature swine, 41 arterial segments removed from each of 17 G?ttingen miniature swines/csk at 6-12 months after birth were examined by light microscopy. Every segment was classified into three types--elastic, transitional, and muscular--according to its histological architecture. Each type was identified on the basis of relative volume and disposition of elastic tissues, collagenous fibers, and smooth muscles in three coats, Tunica intima, Tunica media, Tunica externa. The distribution of each type was demonstrated in a transition from the elastic to the muscular type. The transitional type was designated as a representative type of artery in transitional regions between elastic and muscular types and had some characteristic structures like a mixture of both of them. This type also had longer regions in the back district with the heart as the starting point, such as the Aorta abdominalis, than that of the front. Every artery belonging to the three types had some different structures at different levels, respectively. It was supposed that the histological arrangement of tissues in the walls of a vessel from various parts of the arterial tree would respond properly to the functional demand.     

New mechanisms of pulmonary arterial hypertension: role of Ca²⁺ signaling

Pulmonary arterial hypertension (PAH) is a severe and progressive disease that usually culminates in right heart failure and death if left untreated. Although there have been substantial improvements in our understanding and significant advances in the management of this disease, there is a grim prognosis for patients in the advanced stages of PAH. A major cause of PAH is increased pulmonary vascular resistance, which results from sustained vasoconstriction, excessive pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular stiffness. In addition to other signal transduction pathways, Ca(2+) signaling in pulmonary artery smooth muscle cells (PASMCs) plays a central role in the development and progression of PAH because of its involvement in both vasoconstriction, through its pivotal effect of PASMC contraction, and vascular remodeling, through its stimulatory effect on PASMC proliferation. Altered expression, function, and regulation of ion channels and transporters in PASMCs contribute to an increased cytosolic Ca(2+) concentration and enhanced Ca(2+) signaling in patients with PAH. This review will focus on the potential pathogenic role of Ca(2+) mobilization, regulation, and signaling in the development and progression of PAH.     

Coupled fluid–structure interaction hemodynamics in a zero-pressure state corrected arterial geometry

Hemodynamic conditions in large arteries are significantly affected by the interaction of the pulsatile blood flow with the distensible arterial wall. A numerical procedure for solving the fluid–structure interaction problem encountered in cardiovascular flows is presented. We consider a patient-specific carotid bifurcation geometry, obtained from 3D reconstruction of in vivo acquired tomography images, which yields a geometrical representation of the artery corresponding to its pressurized state. To recover the geometry of the artery in its zero-pressure state which is required for a fluid–structure interaction simulation we utilize inverse finite elastostatics. Time-dependent flow simulations with in vivo measured inflow volume flow rate in the 3D undeformed artery are performed through the finite element method. The coupled-momentum method for fluid–structure interaction is adopted to incorporate the influence of wall compliance in the numerical computation of the time varying flow domain. To demonstrate the importance in recovering the zero-pressure state of the artery in hemodynamic simulations we compute the time varying flow field with compliant walls for the original and the zero-pressure state corrected geometric configurations of the carotid bifurcation. The most important resulting effects in the hemodynamic environment are evaluated. Our results show a significant change in the wall shear stress distribution and the spatiotemporal extent of the recirculation regions.     

Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs?

Histological and electron microscopic studies over the past four decades have highlighted "plump," "enlarged" endothelial, smooth muscle, and fibroblastic cellular elements with increased endoplasmic reticulum, Golgi stacks, and vacuolation in pulmonary arterial lesions in human and in experimental (hypoxia and monocrotaline) pulmonary arterial hypertension. However, the contribution of disrupted intracellular membrane trafficking in the pathobiology of this disease has received insufficient attention. Recent studies suggest a pathogenetic role of the disruption of intracellular trafficking of vasorelevant proteins and cell-surface receptors in the development of this disease. The purpose of this essay is to highlight the molecular regulation of vesicular trafficking by membrane tethers, SNAREs and SNAPs, and to suggest how their dysfunction, directly and/or indirectly, might contribute to development of pulmonary arterial hypertension in experimental models and in humans, including that due to mutations in bone morphogenetic receptor type 2.     

Borderline pulmonary pressures in scleroderma - a ‘pre-pulmonary arterial hypertension’ condition?

Patients with systemic sclerosis may develop borderline pulmonary arterial pressure. The clinical relevance of this condition is not always clear. Reported data support the evidence that this subgroup may represent an intermediate stage between normal pulmonary arterial pressure and manifest pulmonary arterial hypertension, a serious complication in scleroderma. Recognizing the clinical relevance of borderline pulmonary arterial pressure increase in scleroderma patients, future studies should aim for clear evidence for diagnostic and therapeutic algorithms for this population.In their recent study, Visovatti and colleagues [1] present a detailed analysis of patients with borderline pulmonary arterial pressure (PAP) as a subgroup analysis of the DETECT study, providing important clinical data for understanding early pulmonary vasculopathy in patients with systemic sclerosis.In fact, every physician who has observed the dramatic deterioration of patients with pulmonary arterial hypertension (PAH) and successive right ventricular failure would urge for the earlier recognition and therapy of this devastating condition. About 10% of all scleroderma patients may develop PAH [2], which - besides lung fibrosis - represents the most frequent cause of death in this patient population [3]. But can PAH be recognized at an early stage and maybe even prevented?If we assume that the increase of PAP is a process lasting for a longer period of time, there must be a phase of transition from normal (mean PAP ≤20 mmHg) pulmonary hemodynamic conditions to PAH (mean PAP ≥25 mmHg). Patients in this so-called ''borderline'' range may represent the early stage of PAH. Earlier studies found that such patients were more likely to develop pulmonary hypertension than patients with mean PAP ≤20 mmHg, with a hazard ratio of 3.7 [4]. The rate of borderline patients developing PAH was 19% after 3 years and 27% after 5 years. Accordingly, we may argue that borderline PAP is a ''pre-PAH'' condition in scleroderma. Of course, borderline elevation of PAP may be caused not only by pulmonary vasculopathy but also by cardiac or pulmonary co-morbidities [5]. In these cases borderline elevation of PAP may be considered as a general prognostic marker [5,6].The analysis of Visovatti and colleagues [1] includes several clinical (for example, current/past telangiectasis, presence of peripheral edema), laboratory (for example, ACA antibody, NT-proBNP), lung functional (for example, forced vital capacity (percentage predicted)/diffusion capacity for carbon monoxide ratio) and cardiac (for example, tricuspid annular plane systolic excursion) markers that may distinguish scleroderma patients with borderline PAP elevation from those with normal PAP or with manifest PAH. According to this analysis, borderline elevation of PAP in scleroderma patients may represent an intermediate stage in the continuum between normal PAP and manifest PAH.Among the DETECT population, 15% of all patients presented with borderline PAP hemodynamics. Although this number may be different in the general scleroderma population, due to the strict inclusion and exclusion criteria of the DETECT study [7], the borderline population seems to be a substantial subgroup. Unfortunately, follow-up data of the described patients in comparison with normal PAP and manifest PAH patients have not been provided. Such data might impact the development of clinical algorithms regarding further follow-up and treatment of these patients.In addition to the borderline elevation of resting PAP, another specific hemodynamic situation in scleroderma patients needs careful interpretation: exercise-induced PAP increase. Earlier studies showed that this may be a frequent condition among scleroderma patients and clinical deterioration and the development of PAH are frequent in this population [2]. In a recent analysis, a strong correlation between resting and exercise PAP values was evident [5], suggesting that patients with borderline hemodynamics and those with a strong PAP increase during exercise may strongly overlap, closing the gap between these two hemodynamic conditions.The most important question remains open: should targeted PAH therapy be offered to scleroderma patients with borderline PAP or exercise-induced PAP increase? Unfortunately there has been no clinical study investigating patients with borderline PAP so far and only two small studies have selected patients with exercise-induced PAP increase [8,9]. The results of these studies are promising, but need to be confirmed in adequately powered, randomized, prospective trials.Based on a series of studies indicating borderline hemodynamics has an important role in scleroderma patients with regard to the development of PAH and potentially for early treatment, future studies should aim for clear evidence for diagnostic and therapeutic algorithms for this patient population. This may contribute to a substantial prognostic improvement for patients with scleroderma who develop pulmonary vasculopathy     

Biomechanical characterization of ventricular–arterial coupling during aging: A multi-scale model study

Left ventricular–arterial (VA) coupling has been recognized to be of great significance in understanding both the global and local mechanical performance of the circulatory system. In this study, a closed-loop multi-scale model of the human cardiovascular system is established for the purpose of studying the coupled VA hemodynamic changes during aging. Obtained results show that age-associated changes in arterial properties have some negative but relatively small influences on left ventricular (LV) mechanical performance, whereas they progressively increase LV and aortic systolic pressures, and aortic pulse pressure during aging. Wave analysis reveals that increased aortic characteristic impedance and premature wave reflection induced by arterial stiffening are two coexistent factors responsible for aortic systolic hypertension and increased aortic pulse pressure at old age. In contrast, aortic dilatation can partly counteract the negative influences of arterial stiffening. Coupled LV-systolic and arterial stiffening (a constant VA coupling index) well preserves LV mechanical performance given normal LV diastolic function during aging, but with a concomitant further elevation of LV and aortic systolic pressures. Furthermore, it is found that the states of arterial, LV-systolic and diastolic stiffness can be distinguished by investigating the sensitivity of LV-systolic pressure to various cardiac indices.     

What measurements are necessary for a comprehensive evaluation of the peripheral arterial circulation?

Several methods are available to detect atherosclerotic lesions with a severe degree of stenosis (>70%), but the diagnosis of atherosclerotic lesions with no stenosis or with a minor degree of stenosis (<20%), is problematic. Hemodynamics associated with stenotic lesions are well described by the relationship of blood pressure and blood flow velocity, both as a function of time and localization (along the length and cross-section of the vessel). The use of this relationship in the clinic is difficult because no precise information is available about the geometry and branching of arteries, blood viscosity, and the velocity distribution over the cross-sectional area of the blood vessel. Besides, the invasiveness of the technique to measure arterial pressure as a function of time and localization does not allow routine application in patients. Because of these limitations, alternative methods have been developed. The degree and extensiveness of atherosclerotic disease can, for instance, be estimated from the changes in maximum blood flow velocity and in velocity profile, i.e., velocity distribution along the cross-section of the vessel. Moreover, the delay between simultaneously recorded arterial blood flow velocity tracings (pulse-wave velocity determination) is used to assess the elastic properties of the vessel. Changes in velocity profile occur at relatively slight degrees of arterial stenosis (around 20%), so that determination of these profiles along diseased arteries may contribute to the early diagnosis of atherosclerotic lesions. In man, transcutaneous information about the maximum and mean blood flow velocities over the cross-sectional area of the artery as an instantaneous function of time as well as the flow pattern can be obtained online with continuous wave Doppler flowmeters, at least when audio spectrum analysis is used as a processing technique. Velocity profiles can be determined with multichannel pulsed Doppler systems if the resolution of the system is adequate and a sufficient number of sample volumes can be obtained, limiting the interpolation between these samples. The on-line recording of velocity profiles can be facilitated by combining the pulsed Doppler device with either a velocity imaging system or a B-mode scan. In systems with a high resolution (sample distance 0.5 mm), one should be able to detect local disturbances in the velocity profile at the site of the lesion (due to local increases in shear stress) and proximal to the lesion (due to reflections), so that lesions with a minor degree of stenosis can be detected. In resistive systems (e.g., internal carotid arteries) in which the relationship between pressure and velocity changes during the cardiac cycle is relatively simple, the elasticity of the arterial wall can be determined by relating the relative diameter changes of the vessel, determined on-line with multichannel pulsed Doppler systems, to the instantaneous velocity pulse. Although the detection of atherosclerotic lesions at an early stage of the disease with sophisticated Doppler devices looks promising, further clinical evaluation is required.     

Platelet-derived growth factor receptor-β and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study

Introduction

Systemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) carries a poor prognosis, despite pulmonary vascular dilating therapy. Platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR) are potential therapeutic targets for PAH because of their proliferative effects on vessel remodelling. To explore their role in SScPAH, we compared PDGFR- and EGFR-mmunoreactivity in lung tissue specimens from SScPAH. We compared staining patterns with idiopathic PAH (IPAH) and pulmonary veno-occlusive disease (PVOD), as SScPAH vasculopathy differs from IPAH and sometimes displays features of PVOD. Immunoreactivity patterns of phosphorylated PDGFR-β (pPDGFR-β) and the ligand PDGF-B were evaluated to provide more insight into the patterns of PDGFR-b activation.

Methods

Lung tissue specimens from five SScPAH, nine IPAH, six PVOD patients and five controls were examined. Immunoreactivity was scored for presence, distribution and intensity.

Results

All SScPAH and three of nine IPAH cases (P = 0.03) showed PDGFR-β-immunoreactivity in small vessels (arterioles/venules); of five SScPAH vs. two of nine IPAH cases (P = 0.02) showed venous immunoreactivity. In small vessels, intensity was stronger in SScPAH vs. IPAH. No differences were found between SScPAH and PVOD. One of five normal controls demonstrated focally mild immunoreactivity. There were no differences in PDGF-ligand and pPDGFR-b-immunoreactivity between patient groups; however, pPDGFR-b-immunoreactivity tended to be more prevalent in SScPAH small vasculature compared to IPAH. Vascular EGFR-immunoreactivity was limited to arterial and arteriolar walls, without differences between groups. No immunoreactivity was observed in vasculature of normals.

Conclusions

PDGFR-β-immunoreactivity in SScPAH is more common and intense in small- and post-capillary vessels than in IPAH and does not differ from PVOD, fitting in with histomorphological distribution of vasculopathy. PDGFR-β immunoreactivity pattern is not paralleled by pPDGFR-β or PDGF-B patterns. PDGFR-β- and EGFR-immunoreactivity of pulmonary vessels distinguishes PAH patients from controls.     

Do vasoregulatory mechanisms in exercising human muscle compensate for changes in arterial perfusion pressure?

We tested the hypothesis that vasoregulatory mechanisms completely counteract the effects of sudden changes in arterial perfusion pressure on exercising muscle blood flow. Twelve healthy young subjects (7 female, 5 male) lay supine and performed rhythmic isometric handgrip contractions (2 s contraction/ 2 s relaxation 30% maximal voluntary contraction). Forearm blood flow (FBF; echo and Doppler ultrasound), mean arterial blood pressure (arterial tonometry), and heart rate (ECG) were measured. Moving the arm between above the heart (AH) and below the heart (BH) level during contraction in steady-state exercise achieved sudden approximately 30 mmHg changes in forearm arterial perfusion pressure (FAPP). We analyzed cardiac cycles during relaxation (FBF(relax)). In an AH-to-BH transition, FBF(relax) increased immediately, in excess of the increase in FAPP (approximately 69% vs. approximately 41%). This was accounted for by pressure-related distension of forearm resistance vasculature [forearm vascular conductance (FVC(relax)) increased by approximately 19%]. FVC(relax) was restored by the second relaxation. Continued slow decreases in FVC(relax) stabilized by 2 min without restoring FBF(relax). In a BH-to-AH transition, FBF(relax) decreased immediately, in excess of the decrease in FAPP (approximately 37% vs. approximately 29%). FVC(relax) decreased by approximately 14%, suggesting pressure-related passive recoil of resistance vessels. The pattern of FVC(relax) was similar to that in the AH-to-BH transition, and FBF(relax) was not restored. These data support rapid myogenic regulation of vascular conductance in exercising human muscle but incomplete flow restoration via slower-acting mechanisms. Local arterial perfusion pressure is an important determinant of steady-state blood flow in the exercising human forearm.     

Retinoid X receptor agonists impair arterial mononuclear cell recruitment through peroxisome proliferator-activated receptor-γ activation

Mononuclear cell migration into the vascular subendothelium constitutes an early event of the atherogenic process. Because the effect of retinoid X receptor (RXR)α on arterial mononuclear leukocyte recruitment is poorly understood, this study investigated whether RXR agonists can affect this response and the underlying mechanisms involved. Decreased RXRα expression was detected after 4 h stimulation of human umbilical arterial endothelial cells with TNF-α. Interestingly, under physiological flow conditions, TNF-α-induced endothelial adhesion of human mononuclear cells was concentration-dependently inhibited by preincubation of the human umbilical arterial endothelial cells with RXR agonists such as bexarotene or 9-cis-retinoid acid. RXR agonists also prevented TNF-α-induced VCAM-1 and ICAM-1 expression, as well as endothelial growth-related oncogene-α and MCP-1 release. Suppression of RXRα expression with a small interfering RNA abrogated these responses. Furthermore, inhibition of MAPKs and NF-κB pathways were involved in these events. RXR agonist-induced antileukocyte adhesive effects seemed to be mediated via RXRα/peroxisome proliferator-activated receptor (PPAR)γ interaction, since endothelial PPARγ silencing abolished their inhibitory responses. Furthermore, RXR agonists increased RXR/PPARγ interaction, and combinations of suboptimal concentrations of both nuclear receptor ligands inhibited TNF-α-induced mononuclear leukocyte arrest by 60-65%. In vivo, bexarotene dose-dependently inhibited TNF-α-induced leukocyte adhesion to the murine cremasteric arterioles and decreased VCAM-1 and ICAM-1 expression. Therefore, these results reveal that RXR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps of the mononuclear recruitment cascade. Thus, RXR agonists may constitute a new therapeutic tool in the control of the inflammatory process associated with cardiovascular disease.     

Multiple nicotinic acetylcholine receptor α-subunits are expressed in the arterial system of the rat

Neuronal nicotinic acetylcholine receptors (nAChRs) are hetero- and homopentamers built up by nine different alpha-subunits and three different beta-subunits. The subtype composition within the receptor determines ligand specificity, affinity and cation permeability. In this study we focused on the distribution of the ligand binding alpha-subunits in the rat arterial system by means of RT-PCR and immunohistochemistry. Subtypes alpha3, alpha5, alpha7 and alpha10 were found to be expressed by endothelial cells, suggesting that they are equipped both with calcium-preferring (alpha7 homopentamers) and monovalent cation-preferring (heteropentamers containing alpha3- and alpha5-subunits) nAChR channels. All alpha-subtypes except alpha9 were expressed by vascular smooth muscle cells with a highly specific distribution pattern along the vascular tree. While every alpha-subunit except alpha9 was detected in the thoracic aorta, intrapulmonary arterial branches contained only alpha7 immunoreactivity, and other vascular beds held intermediate positions with respect to the extent of alpha-subunit expression. Current knowledge does not allow to correlate these distribution patterns to specific functions, but it can be anticipated that at least some components of nAChR-mediated signalling in the arterial wall are highly specific for individual arteries.     

Long-chain acyl-CoA synthetase 4 modulates prostaglandin E₂ release from human arterial smooth muscle cells

Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. Purified ACSL4 is an arachidonic acid (20:4)-preferring ACSL isoform, and ACSL4 is therefore a probable regulator of lipid mediator production in intact cells. Eicosanoids play important roles in vascular homeostasis and disease, yet the role of ACSL4 in vascular cells is largely unknown. In the present study, the ACSL4 splice variant expressed in human arterial smooth muscle cells (SMCs) was identified as variant 1. To investigate the function of ACSL4 in SMCs, ACSL4 variant 1 was overexpressed, knocked-down by small interfering RNA, or its enzymatic activity acutely inhibited in these cells. Overexpression of ACSL4 resulted in a markedly increased synthesis of arachidonoyl-CoA, increased 20:4 incorporation into phosphatidylethanolamine, phosphatidylinositol, and triacylglycerol, and reduced cellular levels of unesterified 20:4. Accordingly, secretion of prostaglandin E₂ (PGE₂) was blunted in ACSL4-overexpressing SMCs compared with controls. Conversely, acute pharmacological inhibition of ACSL4 activity resulted in increased release of PGE₂. However, long-term downregulation of ACSL4 resulted in markedly reduced PGE₂ secretion. Thus, ACSL4 modulates PGE₂ release from human SMCs. ACSL4 may regulate a number of processes dependent on the release of arachidonic acid-derived lipid mediators in the arterial wall.     

Berberine attenuates hypoxia-induced pulmonary arterial hypertension via bone morphogenetic protein and transforming growth factor-β signaling

Hypoxia-induced excessive pulmonary artery smooth muscle cell (PASMC) proliferation plays an important role in the pathology of pulmonary arterial hypertension (PAH). Berberine (BBR) is reported as an effective antiproliferative properties applied in clinical. However, the effect of BBR on PAH remains unclear. In the present study, we elucidated the protective effects of BBR against abnormal PASMC proliferation and vascular remodeling in chronic hypoxia-induced hearts. Furthermore, the potential mechanisms of BBR were investigated. For this purpose, C57/BL6 mice were exposed to chronic hypoxia for 4 weeks to mimic severe PAH. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased the right ventricular systolic pressure (RVSP), the right ventricle/left ventricle plus septum RV/(LV + S) weight ratio, and the median width of pulmonary arterioles. BBR attenuated the elevations in RVSP and RV/(LV + S) and mitigated pulmonary vascular structure remodeling. BBR also suppressed the hypoxia-induced increases in the expression of proliferating cell nuclear antigen (PCNA) and of α-smooth muscle actin. Furthermore, administration of BBR significantly increased the expression of bone morphogenetic protein type II receptor (BMPR-II) and its downstream molecules P-smad1/5 and decreased the expression of transforming growth factor-β (TGF-β) and its downstream molecules P-smad2/3. Moreover, peroxisome proliferator-activated receptor γ expression was significantly decreased in the hypoxia group, and this decrease was reversed by BBR treatment. Our study demonstrated that the protective effect of BBR against hypoxia-induced PAH in a mouse model may be achieved through altered BMPR-II and TGF-β signaling.