scholarly journals Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension

2012 ◽  
Vol 302 (6) ◽  
pp. L555-L568 ◽  
Author(s):  
Xiao-Ru Yang ◽  
Amanda H. Y. Lin ◽  
Jennifer M. Hughes ◽  
Nicholas A. Flavahan ◽  
Yuan-Ning Cao ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Transient Receptor Potential ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Myogenic Tone ◽  
Hypotonic Solution ◽  
Hypoxia Exposure

Chronic hypoxia causes pulmonary hypertension with vascular remodeling, increase in vascular tone, and altered reactivity to agonists. These changes involve alterations in multiple Ca2+ pathways in pulmonary arterial smooth muscle cells (PASMCs). We have previously shown that vanilloid (TRPV)- and melastatin-related transient receptor potential (TRPM) channels are expressed in pulmonary arteries (PAs). Here we found that TRPV4 was the only member of the TRPV and TRPM subfamilies upregulated in PAs of chronic hypoxic rats. The increase in TRPV4 expression occurred within 1 day of hypoxia exposure, indicative of an early hypoxic response. TRPV4 in PASMCs were found to be mechanosensitive. Osmo-mechanical stress imposed by hypotonic solution activated Ca2+ transients; they were inhibited by TRPV4 specific short interfering RNA, the TRPV blocker ruthenium red, and the cytochrome P450 epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide. Consistent with TRPV4 upregulation, the Ca2+ response induced by the TRPV4 agonist 4α-phorbol 12,13-didecanoate and hypotonicity was potentiated in hypoxic PASMCs. Moreover, a significant myogenic tone, sensitive to ruthenium red, was observed in pressurized endothelium denuded small PAs of hypoxic but not normoxic rats. The elevated basal intracellular Ca2+ concentration in hypoxic PASMCs was also reduced by ruthenium red. In extension of these results, the development of pulmonary hypertension, right heart hypertrophy, and vascular remodeling was significantly delayed and suppressed in hypoxic trpv4−/− mice. These results suggest the novel concept that TRPV4 serves as a signal pathway crucial for the development of hypoxia-induced pulmonary hypertension. Its upregulation may provide a pathogenic feed-forward mechanism that promotes pulmonary hypertension via facilitated Ca2+ influx, subsequently enhanced myogenic tone and vascular remodeling.

scholarly journals Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs

2016 ◽  
Vol 311 (3) ◽  
pp. C482-C497 ◽  
Author(s):  
Jun Zhang ◽  
Wenju Lu ◽  
Yuqin Chen ◽  
Qian Jiang ◽  
Kai Yang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Transient Receptor Potential ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Arteries ◽  
Receptor Potential ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Canonical Transient Receptor Potential ◽  
Transient Receptor

The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca2+ concentration ([Ca2+]i) and store-operated Ca2+ entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca2+] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca2+]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca2+]i signaling axis in PASMCs.

scholarly journals Cytochrome P450 Epoxygenase-Dependent Activation of TRPV4 Channel Participates in Enhanced Serotonin-Induced Pulmonary Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yang Xia ◽  
Lexin Xia ◽  
Zhou Jin ◽  
Rui Jin ◽  
Omkar Paudel ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cytochrome P450 ◽  
Transient Receptor Potential ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Specific Inhibitor ◽  
Receptor Potential ◽  
Inhibitory Effect ◽  
Transient Receptor Potential Vanilloid ◽  
Pulmonary Vasoconstriction

Transient receptor potential vanilloid 4 (TRPV4) is a multi-functional non-selective channel expressed in pulmonary vasculatures. TRPV4 contributes to serotonin- (5-HT-) induced pulmonary vasoconstriction and is responsible in part for the enhanced 5-HT response in pulmonary arteries (PAs) of chronic hypoxia mice. Epoxyeicosatrienoic acid (EET) is an endogenous agonist of TRPV4 and is known to regulate vasoreactivity. The levels of EETs, the expression of cytochrome P450 (CYP) epoxygenase for EET production, and epoxide hydrolase for EET degradation are altered by chronic hypoxia. Here, we examined the role of EET-dependent TRPV4 activation in the 5-HT-mediated PA contraction. In PAs of normoxic mice, inhibition of TRPV4 with a specific inhibitor HC-067047 caused a decrease in the sensitivity of 5-HT-induced PA contraction without affecting the maximal contractile response. Application of the cytochrome P450 epoxygenase inhibitor MS-PPOH had no effect on the vasoreactivity to 5-HT. In contrast, inhibition of CYP epoxygenase or TRPV4 both attenuated the 5-HT-elicited maximal contraction to a comparable level in PAs of chronic hypoxic mice. Moreover, the inhibitory effect of MS-PPOH on the 5-HT-induced contraction was obliterated in PAs of chronic hypoxic trpv4-/- mice. These results suggest that TRPV4 contributes to the enhanced 5-HT-induced vasoconstriction in chronic hypoxic PAs, in part via the CYP-EET-TRPV4 pathway. Our results further support the notion that manipulation of TRPV4 function may offer a novel therapeutic strategy for the treatment of hypoxia-related pulmonary hypertension.

Polycythemia and vascular remodeling in chronic hypoxic pulmonary hypertension in guinea pigs

1991 ◽  
Vol 71 (6) ◽  
pp. 2218-2223 ◽  
Author(s):  
S. P. Janssens ◽  
B. T. Thompson ◽  
C. R. Spence ◽  
C. A. Hales
Keyword(s):  
Pulmonary Hypertension ◽  
Guinea Pigs ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Similar Degree ◽  
Similar Tendency ◽  
Pulmonary Arterial ◽  
Medial Thickening

Chronic hypoxia increases pulmonary arterial pressure (PAP) as a result of vasoconstriction, polycythemia, and vascular remodeling with medial thickening. To determine whether preventing the polycythemia with repeated bleeding would diminish the pulmonary hypertension and remodeling, we compared hemodynamic and histological profiles in hypoxic bled (HB, n = 6) and hypoxic polycythemic guinea pigs (H, n = 6). After 10 days in hypoxia (10% O2), PAP was increased from 10 +/- 1 (SE) mmHg in room air controls (RA, n = 5) to 20 +/- 1 mmHg in H (P less than 0.05) but was lower in HB (15 +/- 1 mmHg, P less than 0.05 vs. H). Cardiac output and pulmonary artery vasoreactivity did not differ among groups. Total pulmonary vascular resistance increased from 0.072 +/- 0.011 mmHg.ml-1.min in RA to 0.131 mmHg.ml-1.min in H but was significantly lower in HB (0.109 +/- 0.006 mmHg.ml-1.min). Hematocrit increased with hypoxia (57 +/- 3% in H vs. 42 +/- 1% in RA, P less than 0.05), and bleeding prevented the increase (46 +/- 4% in HB, P less than 0.05 vs. H only). The proportion of thick-walled peripheral pulmonary vessels (53.2 +/- 2.9% in HB and 50.6 +/- 4.8% in H vs. 31.6 +/- 2.6% in RA, P less than 0.05) and the percent medial thickness of pulmonary arteries adjacent to alveolar ducts (7.2 +/- 0.6% in HB and 7.0 +/- 0.4% in H vs. 5.2 +/- 0.4% in RA, P less than 0.05) increased to a similar degree in both hypoxic groups. A similar tendency was present in larger bronchiolar vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals HMGB1 is mechanistically essential in the development of experimental pulmonary hypertension

2019 ◽  
Vol 316 (2) ◽  
pp. C175-C185 ◽  
Author(s):  
Mao Dai ◽  
Rui Xiao ◽  
Luyao Cai ◽  
Tong Ge ◽  
Liping Zhu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Transient Receptor Potential ◽  
High Mobility ◽  
Receptor Potential ◽  
Neutralizing Antibody ◽  
Right Heart Failure ◽  
Transient Receptor Potential Channel ◽  
Underlying Mechanism ◽  
Akt Phosphorylation ◽  
Hypoxia Exposure

Pulmonary hypertension (PH) is a mortal disease featuring pulmonary vascular constriction and remodeling, right heart failure, and eventual death. Several reports showed that high-mobility group box 1 (HMGB1) appears to be critical for the development of PH; the underlying mechanism, however, has not been revealed. Experiments in the present study demonstrated that HMGB1 levels were elevated in the lung tissue and blood plasma of rats after chronic hypoxia exposure and monocrotaline treatment. HMGB1 was originally located within the nucleus and translocated to the cytoplasm of pulmonary artery smooth muscle cells (PASMCs) upon hypoxia exposure, a process that appeared to be mediated by endogenous H2O2. Exposure to HMGB1 mobilized calcium signaling in PASMCs, a response that was attenuated by extracellular Ca2+ removal, Toll-like receptor 4 (TLR4) inhibition by TAK-242, or transient receptor potential channel (TRPC) suppression with 2-aminoethoxydiphenyl borate (2-APB) and SKF-96365. The sustained phosphorylation of the Akt pathway modulated HMGB1-induced migration of PASMCs. The blockage of HMGB1 with glycyrrhizin or anti-HMGB1 neutralizing antibody attenuated lung inflammation and PH establishment in rats after hypoxia exposure and monocrotaline treatment. The above findings reveal the mechanistic importance of HMGB1 in PH through TLR4- and TRPC-associated Ca2+ influx and Akt phosphorylation-driven PASMC migration.

scholarly journals Expression of store-operated Ca2+ entry and transient receptor potential canonical and vanilloid-related proteins in rat distal pulmonary venous smooth muscle

2010 ◽  
Vol 299 (5) ◽  
pp. L621-L630 ◽  
Author(s):  
Gongyong Peng ◽  
Wenju Lu ◽  
Xiaoyan Li ◽  
Yuqin Chen ◽  
Nanshan Zhong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Pulmonary Veins ◽  
Primary Cultures ◽  
Pulmonary Arteries ◽  
Receptor Potential ◽  
Hypoxic Pulmonary Hypertension ◽  
Fura 2 ◽  
Transient Receptor

Chronic hypoxia causes remodeling and alters contractile responses in both pulmonary arteries and pulmonary veins. Although pulmonary arteries have been studied extensively in these disorders, the mechanisms by which pulmonary veins respond to hypoxia and whether these responses contribute to chronic hypoxic pulmonary hypertension remain poorly understood. In pulmonary arterial smooth muscle, we have previously demonstrated that influx of Ca2+ through store-operated calcium channels (SOCC) thought to be composed of transient receptor potential (TRP) proteins is likely to play an important role in development of chronic hypoxic pulmonary hypertension. To determine whether this mechanism could also be operative in pulmonary venous smooth muscle, we measured intracellular Ca2+ concentration ([Ca2+]i) by fura-2 fluorescence microscopy in primary cultures of pulmonary venous smooth muscle cells (PVSMC) isolated from rat distal pulmonary veins. In cells perfused with Ca2+-free media containing cyclopiazonic acid (10 μM) and nifedipine (5 μM) to deplete sarcoplasmic reticulum Ca2+ stores and block voltage-dependent Ca2+ channels, restoration of extracellular Ca2+ (2.5 mM) caused marked increases in [Ca2+]i, whereas MnCl2 (200 μM) quenched fura-2 fluorescence, indicating store-operated Ca2+ entry (SOCE). SKF-96365 and NiCl2, antagonists of SOCC, blocked SOCE at concentrations that did not alter Ca2+ responses to 60 mM KCl. Of the seven known canonical TRP (TRPC1–7) and six vanilloid-related TRP channels (TRPV1–6), real-time PCR revealed mRNA expression of TRPC1 > TRPC6 > TRPC4 > TRPC2 ≈ TRPC5 > TRPC3, TRPV2 > TRPV4 > TRPV1 in distal PVSMC, and TRPC1 > TRPC6 > TRPC3 > TRPC4 ≈ TRPC5, TRPV2 ≈ TRPV4 > TRPV1 in rat distal pulmonary vein (PV) smooth muscle. Western blotting confirmed protein expression of TRPC1, TRPC6, TRPV2, and TRPV4 in both PVSMC and PV. Our results suggest that SOCE through Ca2+ channels composed of TRP proteins may contribute to Ca2+ signaling in rat distal PV smooth muscle.

scholarly journals Role of platelet-activating factor in pulmonary vascular remodeling associated with chronic high altitude hypoxia in ovine fetal lambs

2007 ◽  
Vol 293 (6) ◽  
pp. L1475-L1482 ◽  
Author(s):  
Christine E. Bixby ◽  
Basil O. Ibe ◽  
May F. Abdallah ◽  
Weilin Zhou ◽  
Alison A. Hislop ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Expression ◽  
High Altitude ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Platelet Activating Factor ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Remodeling ◽  
Mediated Effects

Platelet-activating factor (PAF) is implicated in pathogenesis of chronic hypoxia-induced pulmonary hypertension in some animal models and in neonates. Effects of chronic hypoxia on PAF receptor (PAF-R) system in fetal pulmonary vasculature are unknown. We investigated the effect of chronic high altitude hypoxia (HAH) in fetal lambs [pregnant ewes were kept at 3,801 m (12,470 ft) altitude from ∼35 to 145 days gestation] on PAF-R-mediated effects in the pulmonary vasculature. Age-matched controls were kept at sea level. Intrapulmonary arteries were isolated, and smooth muscle cells (SMC-PA) were cultured from HAH and control fetuses. To determine presence of pulmonary vascular remodeling, lung tissue sections were subjected to morphometric analysis. Percentage medial wall thickness was significantly increased ( P < 0.05) in arteries at all levels in the HAH lambs. PAF-R protein expression studied by immunocytochemistry and Western blot analysis on lung tissue SMC-PA demonstrated greater PAF-R expression in HAH lambs. PAF-R binding (femtomoles per 106 cells) in HAH SMC-PA was 90.3 ± 4.08 and 66% greater than 54.3 ± 4.9 in control SMC-PA. Pulmonary arteries from HAH fetuses synthesized >3-fold PAF than vessels from controls. Compared with controls SMC-PA of HAH lambs demonstrated 139% and 40% greater proliferation in 10% FBS alone and with 10 nM PAF, respectively. Our data demonstrate that exposure of ovine fetuses to HAH will result in significant upregulation of PAF synthesis, PAF-R expression, and PAF-R-mediated effects in pulmonary arteries. These findings suggest that increased PAF-R protein expression and increased PAF binding contribute to pulmonary vascular remodeling in these animals and may predispose them to persistent pulmonary hypertension after birth.

scholarly journals TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension

2013 ◽  
Vol 305 (7) ◽  
pp. C704-C715 ◽  
Author(s):  
Yang Xia ◽  
Zhenzhen Fu ◽  
Jinxing Hu ◽  
Chun Huang ◽  
Omkar Paudel ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Reactivity ◽  
Transient Receptor Potential ◽  
Pulmonary Arteries ◽  
Receptor Potential ◽  
Induced Response ◽  
Transient Receptor Potential Vanilloid ◽  
Hypoxic Pulmonary Hypertension ◽  
Mechanical Coupling ◽  
Pulmonary Vasoconstriction

Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive channel in pulmonary arterial smooth muscle cells (PASMCs). Its upregulation by chronic hypoxia is associated with enhanced myogenic tone, and genetic deletion of trpv4 suppresses the development of chronic hypoxic pulmonary hypertension (CHPH). Here we further examine the roles of TRPV4 in agonist-induced pulmonary vasoconstriction and in the enhanced vasoreactivity in CHPH. Initial evaluation of TRPV4-selective antagonists HC-067047 and RN-1734 in KCl-contracted pulmonary arteries (PAs) of trpv4−/−mice found that submicromolar HC-067047 was devoid of off-target effect on pulmonary vasoconstriction. Inhibition of TRPV4 with 0.5 μM HC-067047 significantly reduced the sensitivity of serotonin (5-HT)-induced contraction in wild-type (WT) PAs but had no effect on endothelin-1 or phenylephrine-activated response. Similar shift in the concentration-response curve of 5-HT was observed in trpv4−/−PAs, confirming specific TRPV4 contribution to 5-HT-induced vasoconstriction. 5-HT-induced Ca2+response was attenuated by HC-067047 in WT PASMCs but not in trpv4−/−PASMCs, suggesting TRPV4 is a major Ca2+pathway for 5-HT-induced Ca2+mobilization. Nifedipine also attenuated 5-HT-induced Ca2+response in WT PASMCs but did not cause further reduction in the presence of HC-067047, suggesting interdependence of TRPV4 and voltage-gated Ca2+channels in the 5-HT response. Chronic exposure (3–4 wk) of WT mice to 10% O2caused significant increase in 5-HT-induced maximal contraction, which was partially reversed by HC-067047. In concordance, the enhancement of 5-HT-induced contraction was significantly reduced in PAs of CH trpv4−/−mice and HC-067047 had no further effect on the 5-HT induced response. These results suggest unequivocally that TRPV4 contributes to 5-HT-dependent pharmaco-mechanical coupling and plays a major role in the enhanced pulmonary vasoreactivity to 5-HT in CHPH.

scholarly journals Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1389
Author(s):  
Solène Barbeau ◽  
Guillaume Gilbert ◽  
Guillaume Cardouat ◽  
Isabelle Baudrimont ◽  
Véronique Freund-Michel ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Drug Targets ◽  
Transient Receptor Potential ◽  
Pulmonary Arteries ◽  
Receptor Potential ◽  
Cell Types ◽  
Major Step ◽  
Membrane Stretch ◽  
Transient Receptor ◽  
Stretch Activated Channels

A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular cells (e.g., contraction, migration, proliferation, production of extracellular matrix proteins, etc.) depend on a key event, i.e., the increase in intracellular calcium concentration ([Ca2+]i) which results from an influx of extracellular Ca2+ and/or a release of intracellular stored Ca2+. Calcium entry from the extracellular space is a major step in the elevation of [Ca2+]i, involving a variety of plasmalemmal Ca2+ channels including the superfamily of stretch-activated channels (SAC). A common characteristic of SAC is that their gating depends on membrane stretch. In general, SAC are non-selective Ca2+-permeable cation channels, including proteins of the TRP (Transient Receptor Potential) and Piezo channel superfamily. As membrane mechano-transducers, SAC convert physical forces into biological signals and hence into a cell response. Consequently, SAC play a major role in pulmonary arterial calcium homeostasis and, thus, appear as potential novel drug targets for a better management of PH.

scholarly journals Upregulation of TRPV4 channels in pulmonary arteries (PAs) contribute to chronic hypoxia induced myogenic tone and pulmonary hypertension

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Xiao‐Ru Yang ◽  
Jennifer M. Hughes ◽  
Yuan‐Ning Cao ◽  
Nicholas A. Flavahan ◽  
Wolfgang Liedtke ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Myogenic Tone

Hypoxia increases AP-1 binding activity by enhancing capacitative Ca2+ entry in human pulmonary artery endothelial cells

2003 ◽  
Vol 285 (6) ◽  
pp. L1233-L1245 ◽  
Author(s):  
Ivana Fantozzi ◽  
Shen Zhang ◽  
Oleksandr Platoshyn ◽  
Carmelle V. Remillard ◽  
Randy T. Cowling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Transcription Factors ◽  
Pulmonary Artery ◽  
Transient Receptor Potential ◽  
Chronic Hypoxia ◽  
Receptor Potential ◽  
Binding Activity

Activating protein (AP)-1 transcription factors modulate expression of genes involved in cell proliferation and migration. Chronic hypoxia increases pulmonary artery smooth muscle cell proliferation by upregulating AP-1-responsive genes encoding for endothelium-derived vasoactive and mitogenic factors implicated in pulmonary hypertension development. The expression of AP-1 transcription factors is sensitive to changes in cytosolic free [Ca2+] ([Ca2+]cyt). Capacitative Ca2+ entry (CCE) via store-operated Ca2+ channels (SOC) is an important mechanism for raising [Ca2+]cyt in pulmonary artery endothelial cells (PAEC). Using combined molecular biological, fluorescence microscopy, and biophysical approaches, we examined the effect of chronic hypoxia (3% O2, 72 h) on AP-1 DNA binding activity, CCE, and transient receptor potential (TRP) gene expression in human (h) PAEC. EMSA showed that AP-1 binding to hPAEC nuclear protein extracts was significantly enhanced by hypoxia, the increase being dependent on store-operated Ca2+ influx and sensitive to La3+, an SOC inhibitor. Hypoxia also increased basal [Ca2+]cyt, the amount of CCE produced by store depletion with cyclopiazonic acid, and the amplitude of SOC-mediated currents ( ISOC). The increases of CCE amplitude and ISOC current density by hypoxia were paralleled by enhanced TRPC4 mRNA and protein expression. Hypoxia-enhanced CCE and TRPC4 expression were also attenuated by La3+. These data suggest that hypoxia increases AP-1 binding activity by enhancing Ca2+ influx via La3+-sensitive TRP-encoded SOC channels in hPAEC. The Ca2+-mediated increase in AP-1 binding may play an important role in upregulating AP-1-responsive gene expression, in stimulating pulmonary vascular cell proliferation and, ultimately, in pulmonary vascular remodeling in patients with hypoxia-mediated pulmonary hypertension.

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