References

Impaired adaptation of intrapulmonary arteries to intrauterine life in the newborn pig exposed to hypoxia an ultrastructural study. Fed. Proc. 1986 45 879a. 2. Ambalavanan N, Philips JB, 3rd, Bulger A, Oparil S, and Chen YF. Endothelin-A receptor blockade in porcine pulmonary hypertension. Pediatr. Res. 2002 52 913-921. 3. Arrigoni FI, Vallance P, Haworth SG, and Leiper JM. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with...

Hypoxiainduced Serotonin Transporter

The serotonin transporter (5-HTT) in pulmonary vascular SMCs has many attributes suggesting that it may be a key determinant of pulmonary SMC proliferation. It belongs to a family of integral membrane proteins responsible for terminating the action of neurotransmitters released from neurons. In addition to 5-HT reuptake into neurons, 5-HTT is responsible for indoleamine uptake by platelets, endothelial cells, and SMCs. These processes result in very low levels of free 5-HT in plasma under...

Does the Cellular Redox State Play a Role in the Regulation of cADPR Accumulation in Pulmonary Artery Smooth Muscle

We were drawn to investigate the possibility that cADPR may be a mediator of HPV for two reasons. As mentioned previously, cADPR had been proposed as an endogenous regulator of RyRs (29, 55), and we had obtained evidence of a role for smooth muscle SR Ca2+ release via RyRs in maintained HPV (23). An additional attraction, however, was the fact that cADPR is a P-NAD+ metabolite. This was because hypoxia had been shown to increase p-NADH levels in all 02-sensing cells studied to date (5, 11, 79,...

Physiology of the Fetal Pulmonary Circulation

Along with the rapid and dramatic progression of lung vascular growth and structure during development, the fetal pulmonary circulation also undergoes maturational changes in function. PVR is high throughout fetal life, especially in comparison with the low resistance of the systemic circulation. As a result, the fetal lung receives, 3-8 of combined ventricular output, with most of the right ventricular output crossing the ductus arteriosus (DA) to the aorta. Pulmonary arterial pressure and...

Zero Stress State is not Permanent

When the blood pressure in a blood vessel is reduced to zero (i.e., when the pressures inside and outside the vessel are the same), the vessel is unloaded. But the vessel may still have a longitudinal residual stress. When the longitudinal stress is released with a cross cut, the vessel shortens. Now if you cut the isolated vessel radially, you will see that it opens up into a sector as shown in Figure 4A. Further cuts will cause only unmeasurable insignificant changes. We may say that as a...

Relating Genetics to Hypoxic Pulmonary Vascular Disease

Studies in transgenic mice suggest that genetic factors might modulate the response to chronic hypoxia. For example, in the absence of hemoxygenase 1, there is reduced production of CO and its associated vasodilatory effects (54). PGI2 synthetase overexpression is protective against the hemodynamic and vascular changes of pulmonary hypertension. Serotonin has been implicated either in the increased vasoreactivity of the Fawn hooded rat and there is attenuated severity of disease in mice lacking...

Regulation of Intracellular [Ca2 in PASMC

Ca2 Proliferation

The lipid membrane is impermeable to cations (e.g., K+, Ca2+) and anions (e.g., CI). Flux of ions across either the plasma membrane or the intraorganelle membrane requires ion channels which selectively allow various ions to go through based on their concentration gradients. Furthermore, ions can be transported across the plasma membrane and the intraorganelle membrane against their concentration gradients by ion pumps (or ion transporters) (10). The concentration of extracellular or...

Relating Acute Vasoconstriction and Vasoactive Mediators to Hypoxic Remodeling

A variety of studies attempted to show how acute vasoconstriction or a direct hypoxic 'injury' initiates the structural changes observed in the pulmonary arteries. Angiotensin II appears to be unimportant as a hypoxic vasoconstrictor but nonetheless is critical to the mechanism responsible for inducing vascular disease because of its biological properties in stimulating vascular smooth muscle cell hypertrophy and proliferation (33). Chronic hypoxia is associated with an increase in angiotensin...

Experimental Studies

A variety of studies in animals have been undertaken to address the mechanisms leading to the evolution of the pulmonary vascular disease in association with hypoxia. It has been noted that at altitude severe pulmonary hypertension may in fact represent a maladaptive response related to the amount ofintrinsic muscle in the vessel wall. The llama, develops little acute or chronic pulmonary hypertension and has the least muscle pulmonary circulation of all species tested (49). In the rat, the...

Concluding Remarks

Ca2+ signaling is a complex process, in which Ca2+ signals are generated by multiple specific Ca2+ transporters, delivered globally or locally, and decoded by different effectors according to the signal amplitude and frequency in their immediate vicinities. In this fashion, a single ionic species can serve as a ubiquitous messenger for numerous cellular functions (e.g., cell proliferation, ion channel regulation, and muscle contraction). In the pulmonary circulation, the research on the...

ILII

Effect of acute hypoxia on K+ currents after selectively blocking Kv1.2 and Kv2.1 channels with specific antibodies. A. Schematic diagram showing how the antibodies (Ab) are delivered to the cytosol through the pipette (left), and block K+ efflux by binding to the C-terminal epitope of the channel polypeptide (right). B Hypoxia-induced inhibition of K+ currents (IK) in cells dialyzed with an anti-Kv1.2 antibody (Ab), an anti-Kv2.1 Ab, or an irrelevant antibody (IgG). * Ps0.001 vs....

Polyamine Transport as a Target for Intervention in Hypoxic Pulmonary Hypertension

Polyamine Transport

The hypoxia-induced increase in polyamine uptake by pulmonary vascular cells raises the question of whether lung cell polyamine regulatory pathways could serve as targets of pharmacologic intervention in hypoxic pulmonary hypertension. Based on the finding that hypoxia decreases ODC activity, ODC blockade would not seem to be a promising approach. Pharmacologic manipulation of polyamine import has not, until recently, been possible owing to the lack of suitable agents. Recently, however, Weeks...

Endotheliumderived Mediators and HPV

Pgf2a Pathway

Although there is strong evidence that the pulmonary vascular endothelium is important, possibly crucial, for development of sustained HPV, and that its action appears to be via an increase in vascular smooth muscle Ca2 sensitivity mediated via RhoA Rho kinase, the mediator responsible has not been identified Fig. 2D . Moreover, the pulmonary endothelium also has a powerful modulatory influence on pulmonary vasomotor tone and vascular resistance via the action of numerous other mediators, and...

Conclusion For Pulmonary Hypertension

The role of growth factors in HPH is an open book, with no ending in sight. As novel vascular growth factors are discovered, and as we learn more about their biological and pathobiological role, we add a new level of understanding in HPH. Undoubtedly, abnormal vascular cell growth is at the center of pulmonary vascular remodeling in pulmonary hypertension Fig. 3 . In the next few years, the elucidation of master control levels of pulmonary vascular remodeling using genomics and proteonomics of...

Microdomains and Organized Signaling in Regulating Kv Channel Function in PASMC

An emerging idea in signal transduction posits the existence of spatially organized complexes of signaling molecules in microdomains 62, 65 of the plasma membrane. Recent studies have focused on the distribution of signaling molecules in caveolae, which are cholesterol and sphingolipid-enriched regions that can form distinct structural invaginations of the plasma membrane and are enriched of the protein caveolin 97 . This notion of signaling microdomains is attractive in that it would account...

Transgenic Mouse Models in Research on Hypoxic Pulmonary Hypertension

During the past few years, many transgenic mouse lines have been established for research on hypoxic pulmonary hypertension 6, 17, 19, 29 . Studies with these mice have provided significant insights into the pathogenesis and potential treatment of hypoxia-induced pulmonary hypertension. Patients with severe pulmonary hypertension have low levels ofprostacyclin synthase PGIS 3 , but the pathogenic significance ofthis deficiency is unclear. Recently, transgenic mice overexpressing PGIS...

The Role of Microcirculation in Hypoxic Pulmonary Hypertension

The role of the capillary blood vessels of the lung in HPH is to reduce the resistance to flow in pulmonary microcirculation. The reason that these vessels can do it is because of their geometry. When the pulmonary capillary blood vessels of cat were photographed on face, they appeared as shown in Figure 1 A. When these capillary vessels were photographed in cross section, they appear as shown in Figure IB. From these photographs one sees that the capillaries form sheets of blood space that are...

Role of Deficient NO and PGI2 in Hypoxic Pulmonary Hypertension

Endogenous NO, derived largely from eNOS, is a potent inhibitor of pulmonary vasoconstriction and HPH 15 . Although eNOS is moderately upregulated in hypoxic hypertensive lungs, and NO suppresses an increased endogenous ET-1-mediated pulmonary vasoconstriction 41, 46, 48 , hypoxic ventilation limits lung NO production 53 . Therefore, deficient production of NO likely plays a role in the development of HPH. Chronic inhaled NO inhibits HPH, and transgenic eNOS-overexpressing mice have increased...

Generation of Transgenic Mice

Transgenic Mice Tre

Application of Transgenic Mouse Technology Transgenic mice are widely used in biomedical research, and numerous applications have been developed, including those used in hypoxic pulmonary hypertension 5, 6, 19, 29 . There are two common uses of transgenic mice in biomedical research. The first is to study the phenotypic effects of transgene expression in the intact animal. In this case, previously defined promoters are often used to control the expression of the transgene in the desired...

Acute Hypoxia Induces Membrane Depolarization by Inhibiting Kv Channels

Pulmonary Artery Pressure Rats

In rat PASMC, acute hypoxia reduces K currents by inhibiting Kv channels Fig. 4Ca 5, 63, 82, 83, 117 . The inhibitory effect of hypoxia on Kv channels appears to be selective to PASMC hypoxia has little effect on Kv currents K V in mesenteric artery smooth muscle cells MASMC isolated from the same rat Fig. 4Cb . The inability of acute hypoxia to reduce K V in MASMC also explains why acute hypoxia has little effect on mesenteric vascular tone 120 . The acute hypoxia-mediated inhibition of Kv...

Mitochondria as Oxygen Sensors

Carotid Body Oxygen Sensing Mech

The mitochondrion's role as the predominant site for 02 consumption and ATP synthesis makes it an obvious candidate site for an 02 sensor. The finding that inhibition of the mitochondrial electron transport chain ETC mimics hypoxia further supports this hypothesis 4 . Indeed ETC inhibitors cause pulmonary vasoconstriction, systemic vasodilation and carotid body activation, a set of responses elicited by few other stimuli save hypoxia 4 . Figure 4 Mitochondria regulate K channel function through...

Treatment of PPHN

Pre And Post Ductal Sats Pphn

In general, management of the newborn with PPHN includes the treatment and avoidance of hypothermia, hypoglycemia, hypocalcemia, anemia and hypovolemia correction of metabolic acidosis diagnostic studies for sepsis serial monitoring of arterial blood pressure, pulse oximetery pre- and post-ductal and transcutaneous PCo2, especially with the initiation of high frequency oscillatory ventilation HFOV . Therapy includes aggressive management of systemic hemodynamics with volume and cardiotonic...

Role for ROS and RNS in Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension

Pulmonary Hypertension Mechanism

For over one hundred years, it has been known that during hypoxia or low P02 the systemic arteries dilate to supply more oxygen to the deprived organ, however, on the contrary the pulmonary arteries constrict to balance the ratio of perfusion to ventilation. This phenomenon is generally termed as acute hypoxic pulmonary vasoconstriction. If HPV is prolonged it leads to pulmonary hypertension PH . PH is characterized by pulmonary arterial vasoconstriction and remodeling. Under physiological...

The Endothelium Ca2 and Ca2 Sensitization

Hpv Biphasic Response

Our studies in rat small pulmonary arteries have shown that the relationship between Ca2 and tension development during sustained HPV 2060 min is not straightforward. Whereas Ca2 j measured using Fura-2 simultaneously with tension shows an initial transient rise followed by a raised but stable plateau, after an initial transient constriction, tension continues to rise progressively without any further change in Ca2 Fig. 1 20, 26, 28 . Moreover, removal ofthe endothelium does not alter the...

Pathogenesis of PPHN

Pphn Pathophysiology

Several experimental models have been studied to explore the pathogenesis and pathophysiology of PPHN 21, 54 . Such models have included exposure to acute or chronic hypoxia after birth, chronic hypoxia in utero, placement of meconium into the airways ofneonatal animals, sepsis and others. Although each model demonstrates interesting physiologic changes that may be especially relevant to particular clinical settings, most studies examine only brief changes in the pulmonary circulation, and...

Clinical Presentation and Evaluation

Clinically, PPHN is most often recognized in term or near term neonates, but clearly can occur in premature neonates as well Table 1 . PPHN is often associated with perinatal distress e.g., asphyxia, low APGAR scores, meconium staining however, idiopathic PPHN can lack signs of acute perinatal distress. PPHN often presents as respiratory distress and cyanosis within 6-12 hrs of birth. Laboratory findings include low glucose, hypocalcemia, hypothermia, polycythemia or thrombocytopenia....

Hypertension And Ihd 2011

Adnot S, Raffestin B, Eddahibi S, Braquet P, and Chabrier P. Loss ofendothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J. Clin. Invest. 1991 87 155-162 2. Christou H, Yoshida A, Arthur V, Morita T, and Kourembanas S. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. Am. J. Respir. Cell. Mol. Biol. 1998 18 768-776. 3. Eddahibi S, Adnot S, Frisdal E, Levame M, Hamon M,...

Additional Heterogeneities

The flow diverting effectiveness ofHPV may depend not only on some of the factors indicated above, but also on the cause of the poor ventilation. For example, in pneumonia, both the host and pathogen mediated inflammatory response would be expected to affect local HPV and or its modulation 6, 41, 91 . In addition, the extent to which the arteries serving the region are mechanically influenced by the alteration in local lung mechanics responsible for the local hypoventilation may have an effect...