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Cellular and Molecular Pathobiology of Pulmonary Hypertension Conference Summary^*

^* From the Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.

Correspondence to: Marlene Rabinovitch, MD, 269 Campus Dr, Room 2245B, Stanford, CA 94305-5162; e-mail: marlener{at}stanford.edu

	Introduction

TOP Introduction Cell-Cell Interactions Cell Diversity and... BMPR-II and Its Ligands... New Diagnostic and Treatment... Future Directions References

 
New knowledge concerning the pathobiology of pulmonary hypertension addressed cell-cell interactions, cell diversity and differentiation, and new attempts at understanding how mutations in a gene such as bone morphogenetic protein receptor (BMPR)-II cause aberrant intracellular signaling, and alter vascular cell structure and function. Common and complementary mechanisms were discussed that will lead to new and innovative hypotheses. Current scientific and therapeutic challenges were identified as well as new opportunities.

	Cell-Cell Interactions

TOP Introduction Cell-Cell Interactions Cell Diversity and... BMPR-II and Its Ligands... New Diagnostic and Treatment... Future Directions References

 
The view that cells other than the cells of the blood vessel wall could influence the pathobiology of pulmonary hypertension was discussed. Specifically, it was shown that, through detailed morphologic studies,¹ epithelial injury results in changes in endothelial cells. One mechanism that was discussed was related to the epithelial injury mediated by tumor necrosis factor-.² This cytokine results in calcium-mediated phospholipase A2 activity, thereby increasing the production of reactive oxygen species (ROS) and H₂O₂. This induces a calcium signal in endothelial cells that modulates the expression of genes such as P-selectin, resulting in inflammatory cell adhesion to endothelial cell surfaces. On the basis of this kind of cross-talk, the proposal was put forth that ligands, such as bone morphogenetic proteins (BMPs) could be released from epithelial cells and act on receptors (eg, BMPR-II) located in vascular cells.

It was further shown that hypoxia-mediated vasoconstriction and vascular remodeling was modulated by ROS produced either locally or by neighboring cells.³ The theme of ROS-mediated gene regulation was pursued in a number of interesting studies. When pulmonary hypertension is induced by exposure to chronic hypoxia or by air embolization, the pulmonary arteries produce less superoxide dismutase and constrict in response to acetylcholine. The mechanism was related to the generation of ROS because it was abolished by a number of selective blockers of free radical production. Further studies have indicated that the mechanism of sustained hypoxic pulmonary vasoconstriction was regulated by redox-sensitive ryanodine receptor-mediated Ca signals. The Gp-phox knockout mouse that fails to produce nicotinamide adenine dinucleotide phosphate oxidase and generate ROS⁴ fails to develop vascular remodeling in response to chronic hypoxia. Interesting data were presented to indicate how ROS production in the lung could lead to changes in DNA binding sites, such as the hypoxia-inducible factor (HIF)-1 DNA recognition sequence.⁵ This results in a basic shift in a key guanine nucleotide that enables the subsequent recruitment of the transcription factor complex and the induction of HIF-1-responsive genes such as vascular endothelial growth factor (VEGF). However, while free radical production might regulate HIF-1-responsive genes, the lung seems relatively insensitive to hypoxia-mediated induction of widespread angiogenesis. In addition, despite ROS production, when the lung is injured with toxins such as bleomycin, this injury per se is not sufficient to induce severe pulmonary vascular disease. This suggests that, while they are necessary, ROS-mediated mechanisms may not be sufficient to induce pulmonary vascular disease.

A novel role for T cells in pulmonary vascular pathobiology was described. The inhibition of VEGF in athymic mice was associated with widespread inflammation in distal vessels. The injection of splenocytes (T cells) appeared to rescue this condition, indicating that surveillance by T cells may protect against vascular injury and subsequent proliferative remodeling.

Relationships were probed comparing tumor angiogenesis to vascular perturbation in disease. In tumor blood vessels, abnormalities in both the endothelial cells and in the underlying pericytes contribute to the leakiness of these vessels.⁶ Treatment with inhibitors of VEGF result in involution of the tumor vessels, but the underlying extracellular matrix as well as the pericytes appear to remain. This suggests that there can be rapid regrowth of vessels along these "tracks." If the tracks remain after the loss of pulmonary arteries in subjects with pulmonary hypertension, then a new growth of blood vessels may result in a response to agents that induce the regression of pulmonary artery hypertrophy and hypertension. In the HIF-1 knockout mouse, the resorption of vessels is evident between embryonic days 8.75 and 9.25, perhaps as a consequence of the loss of the supporting architecture provided by cells of neural crest origin.⁷

Cell-cell interactions appear to be critical in the recruitment of progenitor cells. In particular, hematopoietic and vascular stem cells are corecruited to sites of injury following the liberation of the s-kit ligand.⁸ How these cells home to the site of injury, engraft, and differentiate is still largely unknown. New studies were introduced suggesting that following pneumonectomy the growth of the remaining lung may be regulated by progenitor cell engraftment. The role of stem cells in pulmonary vascular pathobiology was also addressed.⁹ Evidence that cells expressing markers of fibroblasts and of macrophages can be found in the expanding adventitia of neonatal calf pulmonary arteries exposed to chronic hypoxia was reported. The source of these cells appears to be the angiogenic vessels in the adventitia.

	Cell Diversity and Differentiation

TOP Introduction Cell-Cell Interactions Cell Diversity and... BMPR-II and Its Ligands... New Diagnostic and Treatment... Future Directions References

 
The dual embryologic derivations of the pulmonary circulation need to be considered in understanding the differences in the pathologic features observed in pulmonary arteries of different sizes and locations.¹⁰ The larger arteries develop as a result of angiogenesis from preexisting vessels, but the microcirculation is the product of vasculogenesis from a plexus of mesenchymal cells and hemangioblasts. In keeping with this, the endothelial cells of the microcirculation could be distinguished from those of the larger pulmonary arteries by specific markers such as N-cadherin, but they were also subjected to different shear stress forces and exhibited different gene expression profiles as well as differences in electrical resistance. Thus, it was suggested that the endothelial cells of the plexiform lesion might be different from the endothelial cells of other lesions that are characterized by occlusive neointimal formation, and smooth muscle cell proliferation and migration.

This theme was further developed in studies showing that the phenotype of the microvasculature could be altered by changes in the extracellular matrix. Previous work had indicated that elastase-mediated and matrix metalloproteinase-mediated changes in the extracellular matrix result in vß₃ integrin signaling associated with focal contacts and the induction of the transcription factor Prx1, which is responsible for tenascin C gene expression.¹¹¹² The production and secretion of tenascin C induces further changes in cell shape resulting in the clustering and activation of epidermal growth factor receptors, leading to cell proliferation. Recent studies¹³ have shown that during development microvascular endothelial cells produce tenascin C as they are forming networks of capillaries. Once these networks mature, the microvasculature abruptly ceases the production of tenascin C in association with a rhoA-dependent distribution of actin as longitudinal stress fibers.¹⁴ Interfering with the tenascin dependency of microvascular endothelial cells in development will result in the disruption of the capillary network and the failure of alveolarization. This is evident in the Prx1 knockout mouse¹⁴ and the Fawn hooded rat pup (S. Gebb, PhD; unpublished data 2004) as well as in the mouse with deficiency in endothelial nitric oxide synthase.¹⁵ In the latter mouse, the rescue of alveoli is possible using inhaled nitric oxide (NO) to restore normal NO levels.

Whereas tenascin production ceases in the mature microvascular pulmonary circulation, macrovascular endothelial cells from the proximal muscular pulmonary arteries distribute actin as cortical stress fibers and continue to produce tenascin C in an Rac1-dependent manner. The transfection of the mature microvascular endothelial cells with Rac1 or Prx1 results in a macroendothelial-like phenotype with the induction of tenascin C and the distribution of actin as cortical stress fibers with focal adhesion contacts.

Perturbing the expression pattern of genes during development could be directly related to the development of abnormalities later in life. For example, BMPR-II is extensively expressed in airway epithelial cells as well as in pulmonary vascular endothelial and smooth muscle cells. Thus, a mutation in the BMPR-II could lead to vascular instability or vulnerability to disease in response to specific environmental factors or somatic mutations in other genes. It was shown how a BMPR-II mutation could de-repress Prx1, leading to the up-regulation of tenascin and the development of vascular lesions.

It is of further interest that tenascin C is expressed in the neointima in patients with severe pulmonary vascular disease and that tenascin C can induce the transformation of mesenchymal cells into endothelial cells. This would support a role for tenascin C in the remodeling that might lead to neoangiogenesis in the neointima in a plexiform lesion. Another matrix component that is similar to tenascin in its integrin profile is osteopontin, which is also associated with pulmonary vascular remodeling in the experimental as well as the clinical setting.

The origin of the plexiform lesion is still the subject of debate. The evidence that this lesion may arise de novo is supported by the similarity between these lesions and the hemangioma lesion of Kaposi sarcoma, and the association of a high incidence of advanced pulmonary hypertension with HIV positivity and the antigen HHV8.¹⁶ The intense expression of VEGF and its receptors as well as HIF-1 also supports neoangiogenesis, but the basis for the hypoxia may be the occlusive neointimal formation. Endothelial cells were shown to proliferate in response to shear stress, while endothelial cell apoptosis in small peripheral arteries has been demonstrated in a number of animal studies in experimental pulmonary hypertension.¹⁷¹⁸ Evidence was therefore presented in cell culture studies that a cell that is resistant to apoptosis may be the origin of the proliferating endothelial cells associated with plexogenic lesions.

The evidence that plexogenic lesions may arise as a consequence of the remodeling of vessels that are occluded by neointimal formation is obtained from longitudinal studies in patients with severe pulmonary vascular disease as a result of congenital heart defects.¹⁹²⁰ It has been shown that features of muscularization of distal vessels as well as the medial hypertrophy of muscular arteries and the loss of distal vessels precede neointimal formation that occurs as a result of the proliferation and migration of smooth muscle cells ( actin-positive cells), obliterating and occluding the vessel lumen. In fact, even with the later development of "angiomata," which characterize the plexiform lesion, the majority of vessels in the lung are characterized by obliterative and proliferative -smooth muscle actin-positive cells. It is therefore conceivable that, in some vessels, the neointima could remodel in response to hypoxia and tenascin C, leading to the infiltration of angiogenic channels. This is consistent with observations that even in the plexiform lesion there are cells positive for smooth muscle markers as well as other cells that have not been well-defined in addition to many dysregulated endothelial cells.

	BMPR-II and Its Ligands and Cell Signals

TOP Introduction Cell-Cell Interactions Cell Diversity and... BMPR-II and Its Ligands... New Diagnostic and Treatment... Future Directions References

 
Further studies have addressed the role of BMPR-II and its ligands in endothelial and smooth muscle cell function. It was shown that BMP4 stimulates human pulmonary artery endothelial cell migration and tube formation and inhibits endothelial cell apoptosis. In keeping with this, endothelial cells from patients with primary pulmonary hypertension form poor capillary networks in culture. It follows that the loss of BMP4 would result in apoptosis and reduced distal vascularity. It was therefore a surprising finding that the mouse with a heterozygous loss of BMP4 is protected against hypoxia-induced vascular remodeling.

The behavior of a cell in response to a ligand is a function of the availability of specific receptors. For example, it was shown that transforming growth factor-ß binding to transforming growth factor-RII inhibits endothelial cell proliferation if the activin receptor-like kinase-5 coreceptor is available since this activates Smad 2/3.²¹ In contrast, endothelial cell proliferation and migration will be stimulated if activin receptor-like kinase-1 is available as a coreceptor to induce similar to mothers against decapentaplegic (Smad) 1/5, which inhibits Smad 2/3. Mutations in the BMPR-II in smooth muscle cells cause enhanced activity (phosphorylation) of the mitogen-activated protein kinase (ERK1/2) that is further increased on ligand stimulation. The loss of the BMPR-II results in the enhanced proliferation of smooth muscle cells in response to serotonin, supporting a synergism between the two pathways. The mouse, in which the human BMPR-II mutation is induced postnatally in smooth muscle cells, has quite severe pulmonary hypertension, but little if any vascular remodeling.²² The dissociation between pressure and remodeling suggests that the aberrant gene per se actually "protects" against remodeling in response to the high pressure it induces, and hence a further genetic or environmental modification would be necessary to produce disease. Applications of transcriptional profiling may offer new opportunities to hunt for such genes, and recent studies²³ have shown that this is possible using peripheral cells from patients with pulmonary hypertension.

The role of environmental influences was also briefly addressed. One very intriguing presentation further delineated the connection between HIV and pulmonary hypertension by showing that Macaques infected with the simian immunodeficiency virus or HIV construct developed an arteriopathy in which there was medial hypertrophy, perivascular cuffing by inflammatory cells, neointimal formation, thrombi, and recanalized lumens.

Independent of BMPR II, the roles of the mitogen-activated protein kinase signaling pathway and protein kinase C isoforms were addressed in a variety of models of pulmonary hypertension, as were different ligands such as interleukin-6 and platelet-derived growth factor. The pathology of pulmonary capillary hemangiomatosis and the aberrant genes involved were also subjects that were discussed, primarily because this disease entity is difficult to differentiate from idiopathic pulmonary hypertension.

A transgenic mouse was recently reported²⁴ in which the overexpression of the calcium-binding protein S100A4/ Mts1 (also known as FSP-1), caused severe pulmonary vascular obliterative disease, but only in a small subset (5%) of animals. The increased expression of Mts1 protein is also found in the occlusive neointimal lesions in lung tissue sections taken from patients with advanced vascular disease. It is of further interest that Mts1 is regulated by both the serotonin receptor and transporter, and that the effects of Mts1 appear to be regulated by BMPR-II. All Mts1 overexpressing mice have pulmonary hypertension at rest and more severe pulmonary hypertension in response to several weeks of hypoxia, which reverses minimally after a 3-month period spent breathing room air. Despite this, vascular changes are not significantly different from those in control mice. Microarray data indicate the induction of a gene that can protect against vascular remodeling.^24a It is speculated that this protective mechanism may be dysfunctional in the small percentage of Mts1-overexpressing mice that develop severe vascular disease.

	New Diagnostic and Treatment Opportunities

TOP Introduction Cell-Cell Interactions Cell Diversity and... BMPR-II and Its Ligands... New Diagnostic and Treatment... Future Directions References

 
Advances in imaging will offer new opportunities to diagnose pulmonary vascular abnormalities and evaluate their impact on myocardial function. Right ventricular function as well as left ventricular function can be assessed independently by criteria on MRI,²⁵ angiography, and CT scanning. A keen appreciation of left ventricular functional indexes reflecting impaired diastolic function is necessary to identify and better treat the patient who is at risk. The investigation of new diagnostic modalities was proposed, specifically the detection of matrix metalloproteinase activity in the urine of patients with pulmonary hypertension. Further studies will need to be done to evaluate the information provided by these analyses, and they should be compared to other diagnostic studies such as brain natriuretic peptide levels, as should newly developed tests such as those for Mts1 levels.

The evaluation of the asymptomatic patient with a BMPR-II mutation by exercise testing revealed latent abnormalities related to a heightened reactivity of the pulmonary circulation with exercise.²⁶ Additional genetic analyses revealed at least one family in which there appears to be recessive inheritance of an abnormal gene at a locus not previously ascribed to families with primary pulmonary hypertension.²⁷ Children with advanced pulmonary vascular disease in association with a congenital heart defect do not appear to have mutations related to BMPR-II. Thus, the search for other genes associated with pulmonary hypertension would appear to be a priority. Polymorphisms in prostacyclin synthase have been proposed, but it is likely that other genes are involved as well.

Based on a variety of studies in experimental animals, new treatment modalities were proposed. These included, simvastatin, peroxisome proliferator-activated receptor-a, and endothelin B overexpression, brain natriuretic peptide and angiopoietin.

Therapies need to be proposed and intensively evaluated, and a network should be established in which they can be tested. In keeping with the cell-based gene therapy approach,¹⁷ it was shown that endothelial progenitor cells can be injected into the pulmonary circulation and that reverse fatal pulmonary hypertension in rats as a consequence of monocrotaline injection. This strategy is further improved if the progenitor cells have been engineered to produce endothelial nitric oxide synthase.^27a Other work has shown the efficacy of elastase inhibitors and epidural growth factor receptor blockers in this model.^2828a The mechanism of regression, in both models, involves the induction of apoptosis of smooth muscle cells in the abnormally muscularized and hypertrophied pulmonary arteries and regression of medial wall thickening. This is accompanied by the regression of abnormally deposited elastin and by a return of peripheral arteries to a near-normal level. Other strategies to induce apoptosis have been proposed, including the use of epidermal growth factor receptor blockers, and initial studies show excellent efficacy in the animal model.

	Future Directions

TOP Introduction Cell-Cell Interactions Cell Diversity and... BMPR-II and Its Ligands... New Diagnostic and Treatment... Future Directions References

 
Based on the information provided during this conference, the following are important directions to pursue in the future.

1. Continued intensive biological research, combining information from cultured cells, and from transgenic and other animal models of disease, should lead to a more extensive understanding of the pathways involved in the pathobiology of pulmonary hypertension.
   
2. Strategies aimed at bridging the gap between known genetic mutations and polymorphisms and the environmental factors and end-points of cellular dysfunction leading to pathobiology need to be pursued. Bioinformatics approaches using information from genomic and proteomic analyses will reveal common and intersecting pathways that will no doubt consolidate and extend our current knowledge. Further studies to identify new mutations and polymorphisms are needed.
   
3. The search for new biomarkers of disease might allow us to stratify patients according to the severity of their structural abnormalities and their responsivity to treatment. New imaging modalities should allow us to tailor therapy to those patients in whom cardiac dysfunction is detected, and to evaluate the current impact of therapies on cardiac function.
   
4. Facilitating the translation of therapies with experimental efficacy to the patient population, should be an important mission, with the proviso that those therapies will need to be further refined to realize their ultimate therapeutic potential.
   

	Footnotes

 
Abbreviations: BMP = bone morphogenetic protein; BMPR = bone morphogenetic protein receptor; HIF = hypoxia-inducible factor; ROS = reactive oxygen species; VEGF = vascular endothelial growth factor

	References

TOP Introduction Cell-Cell Interactions Cell Diversity and... BMPR-II and Its Ligands... New Diagnostic and Treatment... Future Directions References

 

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This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rabinovitch, M. Search for Related Content PubMed PubMed Citation Articles by Rabinovitch, M.