Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats

Vascular remodeling, rather than vasoconstriction, is believed to account for high vascular resistance in severe pulmonary arterial hypertension (PAH). We have found previously that acute Rho kinase inhibition nearly normalizes PAH in chronically hypoxic rats that have no occlusive neointimal lesions. Here we examined whether Rho kinase-mediated vasoconstriction was also important in a rat model of severe occlusive PAH. Adult rats were exposed to chronic hypoxia ( approximately 10% O(2)) after subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SUGEN 5416. Hemodynamic measurements were made in anesthetized rats after 2 weeks of hypoxia (early group) and 3 weeks of hypoxia plus 2 weeks of normoxia (late group). Both groups developed PAH, with greater severity in the late group. In the early group, intravenous fasudil was more effective than intravenous bradykinin, inhaled NO, or intravenous iloprost in reducing right ventricular systolic pressure. Despite more occlusive vascular lesions, fasudil also markedly reduced right ventricular systolic pressure in late-stage rats. Blood-perfused lungs from late-stage rats showed spontaneous vasoconstriction, which was reversed partially by the endothelin A receptor blocker BQ123 and completely by fasudil or Y-27632. Phosphorylation of MYPT1, a downstream target of Rho kinase, was increased in lungs from both groups of rats, and fasudil (intravenous) reversed the increased phosphorylation in the late group. Thus, in addition to structural occlusion, Rho kinase-mediated vasoconstriction is an important component of severe PAH in SUGEN 5416/hypoxia-exposed rats, and PAH can be significantly reduced in the setting of a severely remodeled lung circulation if an unconventional vasodilator is used.     

重叠综合征相关性肺动脉高压研究进展

阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea syndrome,OSAS)和 COPD 是常见的呼吸系统疾病,二者并存率很高,称为重叠综合征(overlap syndrome, OS),肺动脉高压(pulmonary hypertension,PH)是两者的常见并发症。COPD 患者伴口咽部为主的上呼吸道阻塞可导致 OSAS 的发生,COPD 相关的 PH 多为香烟烟雾、炎症产物引起内皮损害,致内皮功能失调,慢性低氧导致血管收缩,肺血管重塑导致管腔变小,血管阻力增加,重度肺气肿时肺毛细血管的丧失都与COPD 时的 PH 相关。而 OSAS 主要为间歇性低氧(intermittent hypoxia,IH)状态导致 PH,很多研究显示持续性低氧与 IH 状态可导致 PH,而 OS 与单纯 COPD 或 OSAS 相比,其夜间低氧及高碳酸血症更严重,更易发生 PH,增加病死率。本文将就 OS 导致 PH 的可能发病机制作一综述。     

慢性阻塞性肺疾病合并肺动脉高压的发病机制研究进展

肺动脉高压(pulmonary hypertension,PH)是慢性阻塞性肺疾病(chronic obstructivepulmonary disease,COPD)的一个重要合并症.COPD合并PH是逐渐发生和进展的,最初于运动或睡眠时出现,逐渐发展为休息时即存在PH,运动、睡眠或病情恶化时进一步升高.COPD相关的PH多为轻到中度,但某些COPD患者可表现为"不成比例"的PH.香烟烟雾、炎症产物引起内皮损害,造成内皮功能失调;慢性低氧引起肺血管收缩;肺血管重构导致管腔变小,血管膨胀性降低,阻力增加;重度肺气肿时肺毛细血管的丧失等均与COPD时的PH相关.     

RhoA activation by hypoxia in pulmonary arterial smooth muscle cells is age and site specific

Hypoxia induces vasoconstriction of pulmonary arteries through contraction of smooth muscle cells (SMCs). The GTPase RhoA regulates smooth muscle contractility and actin cytoskeletal remodeling through the Rho-associated kinase (ROCK). We previously found that the postnatal fall in pulmonary vascular resistance was associated with actin cytoskeletal remodeling in porcine pulmonary arterial SMCs (PASMCs) in vivo. Here, we investigated the effects of acute and chronic hypoxia on the morphology and RhoA activity of PASMCs from fetal and neonatal piglets. Acute hypoxia enhanced actin stress fiber formation and RhoA activity in both inner and outer medial PASMCs from the fetus but only in the inner medial PASMCs from normal 3-day-old piglets. The increased stress fiber formation was dependent on Rho and ROCK. In outer medial PASMCs from 14-day-old animals, acute hypoxia decreased RhoA activity. Interestingly, outer medial PASMCs from animals exposed to chronic hypoxia had fewer stress fibers associated with a lower basal RhoA activity. Treatment of PASMCs from normal 3-day-old piglets with Rho or ROCK inhibitors for 24 hours induced a similar morphology. Rac activity was not altered by either acute or chronic hypoxia. These data show that acute hypoxia induces RhoA activation only in PASMCs from young animals, whereas chronic hypoxia selectively downregulates RhoA activity in outer medial PASMCs leading to an altered phenotype.     

Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension

We have found in chronically hypoxic rats that acute intravenous administration of the Rho kinase inhibitor Y-27632 nearly normalizes the pulmonary hypertension (PH) but has no pulmonary vascular selectivity. In this study, we tested if oral or inhaled Y-27632 would be an effective and selective pulmonary vasodilator in hypoxic PH. Although acute oral Y-27632 caused a marked and sustained decrease in mean pulmonary arterial pressure (MPAP), it also decreased mean systemic arterial pressure (MSAP). In contrast, 5 minutes of inhaled Y-27632 decreased MPAP without reducing MSAP. The hypotensive effect of inhaled Y-27632 on hypoxic PH was greater than that of inhaled nitric oxide, and the effect lasted for at least 5 hours. Inhaled fasudil, another Rho kinase inhibitor, caused selective MPAP reductions in monocrotaline-induced PH and in spontaneous PH in fawn-hooded rats, as well as in chronically hypoxic rats. These results suggested that inhaled Y-27632 was more effective than inhaled nitric oxide as a selective pulmonary vasodilator in hypoxic PH, and that Rho kinase-mediated vasoconstriction was also involved in the other models of PH. Inhaled Rho kinase inhibitors might be useful for acute vasodilator testing in patients with PH, and future work should evaluate their efficacy in the long-term treatment of PH.     

Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension

We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null Bmp4(lacZ/+) mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5/8 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH.     

Angiotensin and cytoskeletal proteins: Role in vascular remodeling

Vascular remodeling occurs during normal development and is involved in various physiologic events. However, the adaptive structural changes of the vasculature can also be pathologic, leading to vascular disease such as hypertension, atherosclerosis, and vein graft disease. Preeclampsia may develop as a consequence of inappropriate vascular remodeling during pregnancy. Angiotensin II contributes to vascular remodeling by activating signal transduction cascades that promote vasoconstriction, growth, and inflammation. The cytoskeleton also participates in structural adaptation responses of the vasculature; cytoskeletal filaments may mediate vasoactive responses, transduce mechanical stimuli, and are involved in pharmacologic signal transduction. It has become clear that many of the cytoskeletal changes during vascular remodeling can be induced by angiotensin II. Recently, the small Gprotein Rho has attracted much attention. The Rho/Rhokinase system is activated by angiotensin II, is a prominent regulator of the cytoskeleton, and is involved in pathologic vascular remodeling.     

Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms

Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site- and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.     

Hydralazine does not inhibit canine hypoxic pulmonary vasoconstriction

Clinical experience with hydralazine has led to conflicting data concerning its effect on the pulmonary vasculature. We studied the effects of hydralazine on the hypoxic pulmonary vasoconstrictor response in 9 dogs challenged with inhalation of 10% oxygen in the presence and absence of hydralazine. Prior to administration of the drug, hypoxia increased cardiac output from 174 +/- 13 to 209 +/- 21 ml/kg/min (p less than 0.05) and pulmonary artery pressure from 9 +/- 1 to 19 +/- 1 mmHg (p less than 0.05). After hydralazine, cardiac output rose during normoxia to 275 +/- 30 and during hypoxia to 305 +/- 34 ml/kg/min (p less than 0.05). Pulmonary artery pressure continued to respond to hypoxia, rising from 11 +/- 1 to 21 +/- 1 mmHg (p less than 0.05) in the presence of hydralazine. Hydralazine reduced pulmonary vascular resistance during normoxia from 173 +/- 14 to 136 +/- 13 dynes X s X cm-5 (p less than 0.05) but even after the drug, pulmonary vascular resistance rose sharply during hypoxia. There was no significant difference in the response to hypoxia of pulmonary artery pressure or pulmonary vascular resistance after hydralazine when compared with that before hydralazine. In a second set of 6 dogs, we repeated these experiments but volume-depleted the dogs after the administration of hydralazine to prevent the passive pulmonary vasodilation that occurs because of the rise in cardiac output with the drug. We again found no inhibition of hypoxic pulmonary vasoconstriction by hydralazine. Finally, we administered sodium nitroprusside to 4 dogs using the same model and found a significant inhibition of hypoxic pulmonary vasoconstriction. Hydralazine, unlike nitroprusside, does not inhibit the pulmonary vascular response to hypoxia.     

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

Regional alveolar hypoxia causes local vasoconstriction in the lung, shifting blood flow from hypoxic to normoxic areas, thereby maintaining gas exchange. This mechanism is known as hypoxic pulmonary vasoconstriction (HPV). Disturbances in HPV can cause life-threatening hypoxemia whereas chronic hypoxia triggers lung vascular remodeling and pulmonary hypertension. The signaling cascade of this vitally important mechanism is still unresolved. Using transient receptor potential channel 6 (TRPC6)-deficient mice, we show that this channel is a key regulator of acute HPV as this regulatory mechanism was absent in TRPC6(-/-) mice whereas the pulmonary vasoconstrictor response to the thromboxane mimetic U46619 was unchanged. Accordingly, induction of regional hypoventilation resulted in severe arterial hypoxemia in TRPC6(-/-) but not in WT mice. This effect was mirrored by a lack of hypoxia-induced cation influx and currents in smooth-muscle cells from precapillary pulmonary arteries (PASMC) of TRPC6(-/-) mice. In both WT and TRPC6(-/-) PASMC hypoxia caused diacylglycerol (DAG) accumulation. DAG seems to exert its action via TRPC6, as DAG kinase inhibition provoked a cation influx only in WT but not in TRPC6(-/-) PASMC. Notably, chronic hypoxia-induced pulmonary hypertension was independent of TRPC6 activity. We conclude that TRPC6 plays a unique and indispensable role in acute hypoxic pulmonary vasoconstriction. Manipulation of TRPC6 function may thus offer a therapeutic strategy for the control of pulmonary hemodynamics and gas exchange.     

Constitutive phosphodiesterase activity restricts spontaneous beating rate of cardiac pacemaker cells by suppressing local Ca2+ releases

We hypothesized that activation of angiogenesis by chronic hypoxia may affect vascular resistance and, subsequently, blood pressure levels in spontaneously hypertensive rats (SHRs). Five-week-old prehypertensive SHRs and age-matched normotensive Wistar-Kyoto (WKY) rats (n=8 per group) were maintained under normobaric normoxic or hypoxic (10% O(2)) conditions for 8 weeks. Three weeks later, the systolic blood pressure was lower by 26% in hypoxic SHRs compared to normoxic SHRs (P<0.05) and remained at the normoxic WKY level. Total peripheral vascular resistance, calculated as the mean arterial pressure/cardiac output (assessed by ultrasound imaging and Doppler), was 30% lower in hypoxic than in normoxic SHRs (P<0.001) and returned to WKY levels. Interestingly, chronic hypoxia also significantly reduced systolic blood pressure in adult 12-week-old SHRs with established hypertension; blood pressure was normalized (versus normoxic WKY rats) after 4 weeks of hypoxia. Changes in hemodynamic parameters were associated with activation of proangiogenic pathways. Protein levels of vascular endothelial growth factor (VEGF)-A in the skeletal muscles were increased by 2.2-fold in hypoxic compared to normoxic SHRs (P<0.001). At the end of the hypoxic period, capillary density in the quadriceps muscle was 1.2-fold higher in hypoxic than in normoxic SHRs (P<0.001). Myocardial capillary density and VEGF-A protein contents were also 1.2- and 2.1-fold higher in hypoxic compared to normoxic SHRs (P<0.001 and P<0.05, respectively). Moreover, treatment with neutralizing VEGF-A antibody abrogated the hypoxia-induced angiogenesis and subsequently worsened arterial hypertension. Therefore, our results suggest that chronic normobaric hypoxia (1) activates VEGF-A-induced angiogenesis and thereafter (2) prevents the occurrence of hypertension in young prehypertensive SHRs and (3) normalizes blood pressure in adult SHRs with established hypertension.     

Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia

Localized alveolar hypoxia causes constriction of the small resistance pulmonary arteries, thus diverting the desaturated, mixed-venous blood to better ventilated areas of the lung. Although modulated by endothelial vasoactive substances, the constrictor response to hypoxia is intrinsic to the smooth muscle cell. Ion channels are important elements in two of the three components of the response. Hypoxia inhibits several potassium channels (voltage-gated and TASK), leading to membrane depolarization and calcium entry through L-type channels. It also causes release of calcium from the sarcoplasmic reticulum, with consequent repletion through store-operated calcium channels. Finally, the effect of the rise in cytosolic calcium is amplified by enhanced calcium sensitivity of the actin/myosin interaction, achieved by the hypoxia-induced increase in Rho-kinase activity. The change in oxygen tension that stimulates these three "executive" components is signaled by a change in the redox status of the smooth muscle cell and probably by downstream changes in G-proteins. Ion channels also play a critical role in the vascular remodeling that results in chronic hypoxic pulmonary hypertension, seen when all the pulmonary vascular bed is hypoxic, at high altitude and in patients with chronic lung diseases. The same inhibition of potassium channels and influx of calcium results in high cytosolic levels of potassium and calcium. These, respectively, lead to inhibition of apoptosis and an increase in cellular proliferation. A better understanding of the pathophysiology of hypoxic pulmonary vasoconstriction and vascular remodeling will enable the design of better treatments for hypoxic and other forms of pulmonary hypertension.     

Perinatal hypoxia increases hypoxic pulmonary vasoconstriction in adult rats recovering from chronic exposure to hypoxia

The possibility that perinatal exposure to hypoxia influences the pulmonary vasculature in adults was tested. Rats born in a hypoxic environment were kept in hypoxia for an additional week after birth. The rats were then raised in atmospheric air, and when adult, they were compared with the rats born and raised in air. Rats (10 wk old) of both groups were exposed to 10% O2 for 2 wk. They were then studied immediately after the exposure and after 2 wk of recovery from the sojourn in the hypoxic environment. The experience of perinatal hypoxia did not affect mean pulmonary arterial blood pressure, right ventricle weight, or the number of muscularized peripheral pulmonary vessels. During exposure to chronic hypoxia in adulthood, both groups developed pulmonary hypertension, which was not affected by previous perinatal hypoxia. The pulmonary vascular responses to acute hypoxic challenges were studied in the preparation of isolated perfused lungs. In both groups of rats, perinatally hypoxic and normoxic, the acute hypoxic vasoconstriction was attenuated immediately after the exposure of adult animals to chronic hypoxia. However, during the recovery from this hypoxic sojourn, the rats born in hypoxia were significantly more reactive to acute lung hypoxia than all other groups of rats studied. It is concluded that the experience of a short period of perinatal hypoxia did not affect the development of hypoxic pulmonary hypertension induced in adulthood. It increased, however, the pulmonary vascular reactivity to acute hypoxic stimuli during the period of recovery from a sojourn in the hypoxic environment in adulthood.     

Adipose Tissue Vascularization: Its Role in Chronic Inflammation

In obesity, the vascular complication is a result of insulin resistance, such as decreased capillary recruitment in skeletal muscle from endothelial insulin resistance. Recent progress in the study of obesity-associated inflammation suggests that vasculature dysfunction occurs in adipose tissue before insulin resistance. In obesity, capillary density and function fail to meet the demand of adipose tissue growth. The failure leads to microcirculation dysfunction from an impaired blood perfusion, which results in a local hypoxia response in adipose tissue. The hypoxia response in adipocytes and macrophages is a new cellular basis for the chronic inflammation. The obesity-associated inflammation has both positive and negative effects in the body. At the early stage, it amplifies the hypoxia signal to stimulate vasculature remodeling locally, and promotes systemic energy expenditure against obesity. At the late stage, it causes adipose tissue dysfunction for insulin resistance. These points suggest that in obesity, adipose tissue vascularization controls chronic inflammation and influences systemic insulin sensitivity.     

Molecular determinants of microvascular dysfunction in hypertensive pregnancy and preeclampsia

Preeclampsia is a pregnancy‐related disorder characterized by hypertension and often fetal intrauterine growth restriction, but the underlying mechanisms are unclear. Defective placentation and apoptosis of invasive cytotrophoblasts cause inadequate remodeling of spiral arteries, placental ischemia, and reduced uterine perfusion pressure (RUPP). RUPP causes imbalance between the anti‐angiogenic factors soluble fms‐like tyrosine kinase‐1 and soluble endoglin and the pro‐angiogenic vascular endothelial growth factor and placental growth factor, and stimulates the release of proinflammatory cytokines, hypoxia‐inducible factor, reactive oxygen species, and angiotensin AT₁ receptor agonistic autoantibodies. These circulating factors target the vascular endothelium, smooth muscle and various components of the extracellular matrix. Generalized endotheliosis in systemic, renal, cerebral, and hepatic vessels causes decreases in endothelium‐derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor, and increases in vasoconstrictors such as endothelin‐1 and thromboxane A2. Enhanced mechanisms of vascular smooth muscle contraction, such as intracellular Ca²⁺, protein kinase C, and Rho‐kinase cause further increases in vasoconstriction. Changes in matrix metalloproteinases and extracellular matrix cause inadequate vascular remodeling and increased arterial stiffening, leading to further increases in vascular resistance and hypertension. Therapeutic options are currently limited, but understanding the molecular determinants of microvascular dysfunction could help in the design of new approaches for the prediction and management of preeclampsia.     

Attenuation of pulmonary hypertension secondary to left ventricular dysfunction in the rat by Rho‐kinase inhibitor fasudil

Pulmonary hypertension (PH) in left ventricular dysfunction is attributable not only to backward failure of the left ventricle, but also to increased pulmonary vascular resistance (PVR) in some patients. Recently, Rho‐kinase has been known as a potent growth stimulator and mediator of vasoconstriction, and Rho‐kinase inhibitors could ameliorate PVR, little is known about the role of Rho‐kinase in left ventricular dysfunction‐induced PH. We utilized the ascending aortic‐banded rat and assessed the effect of Rho‐kinase inhibitor fasudil on the development of PH secondary to left ventricular dysfunction. Subsequently, in rats subjected to aortic banding for 6 weeks, there were increases in mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, active RhoA, Rho‐kinase II, Rho‐kinase activity, endothelial nitric oxide synthase (eNOS) and endothelin‐1(ET‐1) concomitant with decreased levels in NO and cGMP in the lung. Treatment with fasudil at a dose of 30 mg/kg/day from days 1 to 28 or from days 29 to 42 decreased the mean pulmonary arterial pressure by 57% and 56%, right ventricular hypertrophy by 31% and 30%, pulmonary arteriolar medial thickness by 50% and 50%, and pulmonary expression of Rho‐kinase II by 41% and 28%, respectively, as well as augmented pulmonary expression of eNOS by 16% and 31% and NO by 50% and 76%, respectively, when compared with the vehicle controls. In conclusion, these results suggest that inhibition of Rho‐kinase may provide therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction. Further translational study in human is needed to substantiate the findings. Pediatr Pulmonol. 2011; 46:45–59. © 2010 Wiley‐Liss, Inc.     

Effects of prostacyclin (PGI2) on hypoxic pulmonary vasoconstriction in the conscious adult sheep

The effects of prostacyclin (PGI2) on alveolar hypoxic pulmonary vasoconstriction were investigated in the conscious adult sheep. In our model, hypoxia also produced increases in pulmonary arterial pressure (PPA) and pulmonary vascular resistance (PVR), indicating pulmonary vasoconstriction. PGI2 was injected rapidly as a 0.5 microgram/kg bolus via the right atrium in five sheep during normoxia and hypoxia. During normoxia, PGI2 increased PPA and cardiac output, and decreased systemic arterial pressure (PSA), systemic vascular resistance (SVR) and PVR. Left atrial pressure did not change. During hypoxia following PGI2 administration, PPA decreased, CO increased, and PVR decreased, suggesting dilator action on the pulmonary resistance vessels. As the same time PSA and SVR decreased, suggesting dilator action on the systemic resistance vessels. However, the degree of the decline in PVR caused by PGI2 was much greater during hypoxia than during normoxia. The decreases in PSA and SVR induced by PGI2 were not significant between hypoxia and normoxia. These findings confirm that PGI2 decreases pulmonary and systemic vascular resistances in normoxic and hypoxic sheep. Moreover, during hypoxia, associated with the increased PPA and PVR, the administration of PGI2 appears to be particularly effective in "normalizing" these parameters.     

Endothelial modulation of pulmonary vascular tone.

Pulmonary endothelial cells normally synthesize prostacyclin (PGI2) and nitric oxide (NO), which are both potent vasodilators. Although PGI2 is largely used to treat patients with severe pulmonary hypertension, its role in the physiology and pathophysiology of the pulmonary circulation is still debated. NO, which is now considered as the endogenous nitrovasodilator, is perhaps more involved than PGI2 in the mechanisms that modulate pulmonary vascular tone in health and disease. There is evidence to suggest that background release of NO contributes to the normally low pulmonary vascular tone in normoxia. Although there are theoretical grounds to hypothesize that hypoxia reduces the synthesis of NO, lack of the latter does not seem to account for the acute hypoxic pulmonary vasoconstriction. Instead, there is evidence to suggest that NO activity is increased in order to modulate the pulmonary vasopressor response to acute alveolar hypoxia. However, more consistent, concerning the role of NO, are data gathered from studies performed in chronic hypoxic conditions. Both experimental data and studies performed in man demonstrate impairment of NO synthesis and/or release in chronic hypoxic pulmonary hypertension. The impaired NO production, whilst reducing the ability of the pulmonary vasculature to relax, also favours the occurrence of excessive pulmonary vasoconstriction. Lack of NO synthesis might also permit mitogenesis and proliferation of various cell types within the vascular wall. We hypothesize that functional alterations of pulmonary endothelium are likely to affect both reactivity and growth of pulmonary vessels. In this respect, NO probably has a pivotal role in modulating pulmonary vascular tone and controlling pulmonary vascular remodelling in health and disease.     

NOX4和eNOS在小鼠慢性缺氧肺血管重塑中的表达及意义

目的观察内皮型一氧化氮合酶（eNOS）和NOX4在小鼠慢性缺氧肺动脉高压形成过程中的改变。方法用HE染色法和免疫组织化学法观察C57BL／6J小鼠在常氧和慢性持续缺氧（10±0．5％O2）1、3、7、14d后肺血管的改变及非肌型小血管d．SMA和eNOS蛋白表达的改变。用Real TimePCR法检测各组小鼠肺组织中eNOS和NOX4mRNA的含量。结果C57BL／6J小鼠慢性缺氧后肺小动脉血管管壁增厚、肺泡内肺动脉d—SMA表达增加,肺组织eNOS和NOXdmRNA以及肺动脉内皮细胞eNOS蛋白的表达随缺氧时间延长进行性升高。结论eNOS和NOX4可能在慢性缺氧肺动脉高压的发病机制中发挥重要作用。