Pulmonary hypertension is a pathophysiologic process characterized by progressive elevation of pulmonary vascular resistance and right heart failure, which is a common complication of many diseases. Pulmonary hypertension with no apparent causes (unknown etiology) is termed primary pulmonary hypertension or, more recently, idiopathic pulmonary arterial hypertension (IPAH). Before the availability of disease-specific (targeted) therapy (through the mid-1980s) the median life expectancy from the time of diagnosis in patients with this disease was 2.8 years.1-3 Modern treatment has markedly improved physical function and has extended survival, and the 5-year mortality is 50%.1 Although there is already more than 100 years of research history, the mechanisms of this disease are still not very clear.2 Recently, with the development of cell biology and molecular genetics, further research into the mechanisms responsible for pulmonary hypertension have been possible, which has helped in its diagnosis and treatment. It is believed that the mechanisms of pulmonary hypertension can not only be described by pathophysiology but involve multiple factors (pathways) like cellular, humoral and molecular genetics, etc. The increased contraction and remodeling of blood vessels and thrombosis are the major pathophysiological basis for the development of pulmonary hypertension.3 Endothelial cells, smooth muscle cells, fibroblasts and platelets all play important roles in the development of pulmonary hypertension. In addition, vasoconstrictive and vasodilating factors, proliferative stimulating and inhibiting factors, coagulating and anti-coagulating substances and different vasoactive substances are involved in its development. Currently, there is extensive work being done on the role of genetic factors in the development of pulmonary hypertension.4 CELLULAR MECHANISMS AND PULMONARY HYPERTENSION The pulmonary vascular remodeling is the major pathological basis of pulmonary hypertension. The structural changes in all three layers (inner, medial and external) of the pulmonary vascular wall have significant meaning in the incidence, development and recovery of the pulmonary hypertension. Endothelial cells An intact vascular endothelium, under normal physiological conditions, plays a very significant role in maintaining the phenotype of smooth muscle cells and the structure of blood vessels. Some abnormal conditions like hypoxia, mechanical injuries, inflammations, drugs and toxins, etc. affect the structure, function and metabolism of endothelial cells, which are the initial (primary) causes of pulmonary hypertension.5 The damage to the endothelium affects its barrier function and damages its link to smooth muscle cells. It also disturbs the equilibrium of the vasoactive substances produced by the endothelium and pulmonary circulation and their regulation of smooth muscle cells, which in turn promote the proliferation of smooth muscle cells and finally modulate the structure of pulmonary vessels. Endothelial damages not only causes disturbances in proliferation and apoptosis but also affect the coagulation of blood.6 In 90% of the lesions, endothelial cells do not express transforming growth factor (TGF)-β2 receptors, which suggests that tumor inhibiting genes are responsible in the development of IPAH.7 Smooth muscle cells During pulmonary artery hypertension, the static tunica media of smooth muscle cells are transformed to a proliferative synthetic state. The smooth muscle cells proliferate and enlarge resulting in hypertrophy of the tunica media. Moreover, the precursor cells of smooth muscle (like intermediate cells and pericytes), which do not differentiate under normal condition, differentiate into new smooth muscle cells. The partial muscular arteries and non muscular arteries get muscularisation which forms new muscular arteries.8 Our previous studies, as well as others, showed that the proliferative index (PI), the apoptotic indexes (AI) and the ratio of PI and AI of the pulmonary artery smooth muscle cells in rats with pulmonary hypertension were higher than those of normal rats. This indicates that hyperplasia and apoptosis of smooth muscle cells of the pulmonary artery occurs during the pulmonary vascular structural remodeling and the imbalance of hyperplasia and apoptosis also take part in the process. Moreover, caspases-3, bcl-2 and NF-κB genes take part in the regulatory mechanism for the smooth muscle cell apoptosis.9,10 Pulmonary smooth muscle cells also synthesize and secrete different vasoactive substances which regulate the pulmonary vascular structural remodeling and the pulmonary hypertension. Fibroblast The proliferation of the fibroblasts in the outer layer of blood vessels, and the abnormal deposition of connective tissues and the changes in extracellular matrix (ECM) are important components for pulmonary vascular structural remodeling. ECM includes collagen, elastin, etc. Our research team recently found that the expression of pulmonary artery collagen I, collagen III, procollagen I mRNA and procollagen III mRNA in rats with pulmonary hypertension were significantly elevated compared with the normal rats. The positive signals were mainly located in the media and adventitia of median and small pulmonary arteries. The expression of collagen degradation regulatory enzymes, tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA, metalloproteinase-1 (MMP-1) mRNA and the ratio of TIMP-1 and MMP-1 in the pulmonary artery were elevated in rats with pulmonary hypertension. These results suggested that with the development of pulmonary hypertension, collagen, as an important component of extracellular matrix, accumulated resulting from increased synthesis and decreased degradation of collagen.11 Our research also showed that elastin, another important ECM component, was also increased in hypoxic pulmonary hypertensive rats. Additionally, after 1 week of hypoxia the inner elastin lamina of the pulmonary artery of rats became thinned and the thickness of the inner elastin lamina was inversely proportional to the pulmonary artery pressure,12 which indicated that the changes in elastin also participated in the development of pulmonary hypertension. Platelets and thrombosis Functional disturbance of platelets and thrombosis play an important role in the development of IPAH. The damage to the endothelium of pulmonary blood vessels induces the activation and agglutination of platelets. The abnormality in the thrombomoduling system and fibinolysis system induce in situ thrombosis in the pulmonary artery.13 Platelets not only have anti-coagulant function but also produce constriction and remodulating active substances which cause remodulating of pulmonary blood vessels. Inflammatory cells The level of inflammatory cell factors like anti-nuclear antibody (ANA), interleukin (IL)-1 and IL-6 are found to be increased in some IPAH patients. Histology showed infiltration of macrophages and lymphocytes which indicated inflammatory cells might take part in the development of IPAH.14 Moreover, an inflammatory reaction plays a role, to some extent, in the development of pulmonary hypertension induced by connective tissue diseases and HIV infection. It is found that the immunosuppressive treatment is beneficial in some cases of lupus induced-pulmonary hypertension MOLECULAR MECHANISMS OF PULMONARY HYPERTENSION Endothelial cells, smooth muscle cells, fibroblasts, platelets and macrophages associated with blood vessels can produce different vasoactive substances. Under normal condition these substances exhibit a dynamic equilibrium; maintain the normal physiological structure and function of pulmonary vessels. The external stimuli (like high pulmonary blood flow, hypoxia and toxins) disturb the equilibrium and induce thrombosis, constriction and pulmonary vascular structural remodeling, which is an important mechanism in the development of pulmonary hypertension. Nitric oxide (NO) NO is closely related to the development of pulmonary hypertension. There exist different opinions regarding the role of NO in pulmonary hypertension. While not all conclusions are accordant. Most researchers believe that the expression of NO synthase (NOS) decreases during pulmonary hypertension resulting in a decrease in NO synthesis and, according to etiology and disease severity, the changes in NO levels also differ accordingly.15 Our research team, as well as others, found that long-term inhalation of NO or use of NO precursor L-arginine (L-Arg) or NO donor nitroglycerin alleviated pulmonary hypertension as well as pulmonary vascular structural remodeling in the hypoxic rats along with an increase in plasma NO. In contrast, NOS inhibitor significantly aggravated pulmonary vascular structural remodeling with downregulation of the endogenous NO/NOS pathway, which indicated NO played an important regulatory role in the development of pulmonary hypertension and pulmonary vascular structural remodeling.16,17 Recently, many hospitals reported the uses of NO inhalation, NO donors and precursor in the treatment of pulmonary hypertension and the effective treatment. Carbon monoxide (CO) Endogenous CO is mainly produced by the degradation of heme in the presence of heme oxygenase (HO). It relaxes the blood vessels and inhibits the proliferation of smooth muscle cells of blood vessels. Recent studies showed that there was the expression of HO in the smooth muscle cells and endothelial cells of pulmonary vessels, which indicated pulmonary circulation was one of the important places for production and release of endogenous CO. Our research team found that the CO/HO-1 system was increased in a time-dependent double-peak manner in hypoxic pulmonary hypertensive rats.18 For example, the content of CO in lung homogenates of rats from hypoxia day 1 and hypoxia day 3 groups was markedly increased compared with that of normal controls, while the content of CO in lung homogenates in the rats of hypoxia day 7 decreased to the baseline. Administration of zinc protoporphyrin (ZnPP), an inhibitor of HO-1, in the hypoxic rats decreased the content of CO in lung homogenate, decreased the apoptosis of the pulmonary artery smooth muscle cells and enhanced the proliferation of pulmonary artery smooth muscle cells and thus worsened hypoxic pulmonary hypertension and pulmonary vascular structural remodeling. Meanwhile, exogenous supply of CO had an adverse action.19 These results show that up-regulation of the CO/HO pathway plays an important role in the regulation of hypoxic pulmonary hypertension. Hydrogen sulfide (H2S) After the discovery of the role of NO and CO, H2S, known as toxic gas for a long time, is also described as a biologically active substance. It can be endogenously generated from cysteine in a reaction catalyzed by cystathionine β-synthesis (CBS) and cystathionine γ-lyase (CSE). The data from our research team, as well as others, demonstrated that H2S exhibited similar functions as NO and CO in the body, such as relaxation of blood vessels, inhibition of the proliferation of smooth muscle cells20 and promotion of the apoptosis of smooth muscle cells, etc. We also reported that H2S played a important role in pathophysiological processes of cardiovascular diseases, such as hypertension, pulmonary hypertension, shock and myocardial injury, etc. Our research team discovered that both the gene expression and activity of CSE were suppressed in lung tissues, and the plasma level of H2S was decreased under hypoxia. Furthermore, supplement of H2S donor molecules opposed the elevation of pulmonary arterial pressure and lessened the pulmonary vascular structure remodeling during hypoxic pulmonary hypertension, while DL-propargylglycine (PPG), a CSE inhibitor, aggravated hypoxic pulmonary hypertension. This indicates that the H2S/CSE pathway plays a significant role in the regulation of hypoxic pulmonary hypertension.21,22 NO, CO and H2S are three gaseous signaling molecules that have complicate interrelations in the regulation of pulmonary hypertension.23,24 Since 1987, NO, CO and more recently H2S, the endogenous gas molecules produced from metabolic pathway, have been recognized respectively as signal molecules involved in the regulation of homeostasis and to play important roles under physiological and pathophysiological conditions. The research into these endogenous gas signaling molecules opened a new avenue in life science. The biological regulatory effects of other endogenous gas molecules, which have previously been regarded as metabolic waste, are now a field of investigation in the life sciences and medicine. In recent years, we began to pay attention to the effects of endogenous sulfur dioxide (SO2) and its derivatives on mammalian and human physiology. SO2 can be produced endogenously from normal metabolism of sulfur containing amino acids. L-cysteine is oxidized via cysteine dioxygenase to L-cysteinesulfinate and the latter can proceed through transamination by glutamate oxaloacetate transaminase (GOT) to β-sulfinylpyruvate which decomposes spontaneously to pyruvate and SO2. During oxidative stress in mammals activated neutrophils can convert H2S to sulfite through a reduced form of a nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent process. Recently, our research team showed that SO2 could be endogenously generated in cardiovascular tissues and could exert important cardiovascular effects, such as vasorelaxant and negative inotropic effects. Moreover, SO2 might play a considerable role in the regulation of systemic circulatory pressure, pulmonary circulatory pressure and vascular structural remodeling in the pathogenesis of hypertension and hypoxic pulmonary hypertension. More studies of the significance of endogenous SO2 in the cardiovascular system under physiological and pathophysiological conditions need to be conducted.25-27 Vasoactive peptides and others vasoactive substances The arachidonic acid metabolic products include prostaglandin E1 (PGE1), PGE2, PGI2 and thromboxane. Among them, PGE2 and thromboxane constrict blood vessels whereas PGE1 and PGI2 dilate blood vessels. PGI2 has strong vasorelaxative effects. It inhibits proliferation of smooth muscle cells and agglutination of platelets. Disturbance in the metabolism of arachidonic acid and reduction in the expression of PGI2 synthesis enzymes occur in pulmonary hypertensive patients.28 Currently, PGI2 and similar functioning substances are successfully used in the treatment of pulmonary hypertension29 and in many countries it is recommended for treatment. In 1993, a new vasoactive polypeptide in chromaffin hemangioma called adrenomedullin (ADM) was found. It has vasorelaxative and hypotensive effects and also inhibits migration and proliferation of smooth muscles of blood vessels. There are different kinds of ADM receptors expressed in pulmonary tissues that combine with specific high affinity binding sites on ADM. The expression of ADM and its receptors increase in hypoxic hypertensive rat lung tissue. Serum ADM levels are also elevated. Our research team and others found that chronic infusion of ADM significantly decreased mean pulmonary artery pressure in hypoxic rats, lessened the muscularization of small pulmonary vessels, attenuated relative medial thickness and relative medial area of pulmonary arteries and alleviated the ultrastructural changes in pulmonary arteries of hypoxic rats. ADM inhibited the proliferation of pulmonary artery smooth muscle cells. Meanwhile, plasma proadrenomedullin N-terminal 20-peptide (PAMP) concentration and the expression of PAMP protein and mRNA in pulmonary arteries in rats with hypoxia treated with ADM were markedly decreased compared with the untreated hypoxic group. The results suggest that ADM ameliorates the development of hypoxic pulmonary vascular structural remodeling. Intramolecular regulation of ADM might play an important role in the regulation of hypoxic pulmonary hypertension by ADM.30,31 Recent studies showed that inhalation of ADM in IPAH patients reduced pulmonary artery pressure but did not change systemic arterial pressure and heart rate.32 This indicated that ADM could possibly become a new drug for the treatment of pulmonary hypertension. Endothelin-1 (ET-1) was discovered in 1988 and is a vasoconstrictive substance. ET stimulates and proliferation of cultured pulmonary artery smooth muscle cells in vitro. Its function is mediated by ETA and ETB receptors. Our research team and others found that ET precursors and ET-1, as well as the expressions of mRNA for ETA and ETB receptors, are significantly increased in the pulmonary arteries and lung tissues of pulmonary hypertensive rats.33 The ET receptor antagonist bosentan improves the hemodyanamics and functions in pulmonary hypertensive patients and is currently a recommended treatment for pulmonary hypertension in many countries.34 Angiotension (AT) is changed to AT II in the presence of angiotension trasferase, which is a strong vasoconstrictive substance. It also stimulates the proliferation of the smooth muscle cells of pulmonary vessels. It is already proven that angiotension trasferase antagonists, not only decrease pulmonary blood pressure, but also improve structural remodeling of pulmonary vessels.35 AT II mediates the high pulmonary blood flow-induced pulmonary vascular structural remodeling. 5-Hydroxytryptamine (serotonin, 5-HT) can constrict blood vessels and also stimulate the proliferation of smooth muscle cells. A significant raise of 5-HT is seen in pulmonary hypertensive patients. In 1999, Eddahibi and colleagues36 found that there was a significant raise in the expression of the 5-HT transporter in response to hypoxia in pulmonary smooth muscle cells. The deletion of the 5-HT transporter gene significantly protects from pulmonary hypertension in hypoxic rats. In IPAH patients, the 5-HT transporter shows polymorphism, which makes pulmonary artery smooth, cells sensitive to 5-HT's proliferation function.37 In addition, platelet-derived growth factor, vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor, TGF, and the platelet-activating factor, urotensin, etc. may be involved in the development of pulmonary hypertension. Potassium channel The voltage dependent potassium channel (Kv, a subtype of potassium channel) is the major potassium channel which is responsible for the contraction of pulmonary artery smooth muscle cells. The inhibition of Kv results in a reduction in outflow of potassium from cells, which causes of depolarization of cell membrane and then the opening of calcium channels increase the calcium level in the cytoplasm, which resultes in vasoconstriction. The disturbance in the Kv channel plays an important role in the pathogenesis of IPAH. Selective Kv1.5 expression is reduced in IPAH patients, accompanied by Kv functional impairment, which leads to membrane depolarization and vasoconstriction.38 Dexfenfluraine plays a role in the treatment of pulmonary hypertension. This drug inhibits the activity of the Kv2.1 channel, which indicates potassium channel participates in the incidence of pulmonary hypertension.39 Potassium channels represent a new treatment target with potential therapeutic value for pulmonary hypertension patients. The regulation in the expression or activity of potassium channels can affect both pulmonary vascular tension and structure. GENETIC ISSUES IN PULMONARY HYPERTENSION Dresdale and colleagues40 discovered in 1954 that IPAH has genetic tendency. Later, a series of researches found that 6% of IPAH patients had a familial incidence and its clinical and pathological characteristics are similar to Sporadic IPAH patients. Based on the research of the families of IPAH patients, it was found that IPAH was an autosomal dominant inherited disease. But only 10%— 20% of the related mutation carriers show the features of pulmonary hypertension. The explication of features of pulmonary hypertension is more often seen in females than in males. Future generations of IPAH patients will gradually advance to a serious condition or there may be a skipped generation. In 1997, Morse et al41 found a susceptible gene located at 2q 31-33.41 On this basis, in 2000 Deng42 and Lane43 independently determined that the gene mutations in the bone morphogenetic protein receptor II (BMPR2) are one of the major causes in the development of IPAH. Currently, it is believed that a mutation in the BMPR2 gene causes a functional defect in BMPR2 receptors which is important in the development of IPAH. Germline mutations in the gene coding for the BMPR2 are present in more than 70% of familial pulmonary arterial hypentension (IPAH) and up to 26% of IPAH.44 Bone morphogenetic protein (BMP) belongs to the TGF-beta super family, and is synthesized and secreted by smooth muscle cells and endothelial cells. It mainly regulates those cells which exhibit major function in the embryonic development and stativity of tissues and inhibits proliferation of vascular smooth muscle cells and induces apoptosis. Similar to TGF-β, the regulatory signal transduction pathways of BMP involve a BMP type I receptor (BMPR1a and BMPR1b) and a BMP type II receptor (BMPR2). The type II receptor is the activator of the type I receptor, the two receptors form a complex unit. They activate Smad signaling protein and LIM-kinase to regulate gene transcription and maintain blood vessels.45 There are 46 types of BMPR2 gene mutations, 60% of which may lead to early termination of transcription. A point mutation and an anomaly in the structural domain of BMPR2 kinase may inhibit its receptor functions, rendering it unable to form a heterologous dimer complex or to lose kinase activity and block the signaling pathway. This can lead to excessive cell proliferation and apoptotic inhibition causing vascular structural remodeling and pulmonary hypertension. CONCLUSIONS Though the pathogenesis of most forms of pulmonary hypertension is unknown, there have been many recent developments, especially pertaining to the molecular genetics and cell biology of pulmonary hypertension. Since the range of medical conditions and environmental exposures associated with pulmonary hypertension is wide, it is difficult to envision a unifying pathogenic mechanism. Although there probably are genetic determinants, environmental exposures and acquired disorders that predispose patients to pulmonary hypertension, it is clear that none of the factors described in this review are sufficient alone to activate the pathways essential to the development of this vascular disease.
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Feb 25, 2022
Helen Christou + 1
Open Access