Vascular Biology
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Basic Science Research
Vascular Biology Group |
| Mission Statement:
Pulmonary vascular disease is a growing problem in many systemic diseases. In disease states, such as scleroderma and hemolytic anemias, in which patient survival has increased dramatically in recent years, pulmonary complications, especially vascular, have become the leading cause of morbidity and mortality. In addition, the development of pulmonary vascular disease associated with left ventricular diastolic dysfunction is increasing dramatically. The mechanisms involved in development of pulmonary vascular disease in any of these states is not well-understood; thus, the object of our studies is to define mechanisms and molecules essential for the development of these vascular abnormalities and use them to try to direct new therapies. Lastly, each of these entities can be associated with relative or absolute hypoxemia; thus, we have been investigating the effects of hypoxia on pulmonary vascular endothelium and methods to mitigate its effect. Background: Sickle cell anemia: We have found that in the pulmonary vascular disease (ACS and/or PH) associated with SCD there is altered expression of endothelial cell (EC)-derived vasoactive molecules, such as endothelin (ET-1) and NO. In addition, there is occurrence of an oxidative state and production of oxidative metabolites of NO, particularly peroxynitrite. Similar results have been observed in our transgenic mouse model of sickle cell disease as well as in humans with ACS. We are screening all sickle cell patients at BMC for evidence of PH (ECHO) and have recently published observations characterizing each phenotype (pulmonary vascular disease vs. LV dysfunction) biochemically and via genomics and proteomics. See the sickle cell link (Dr. Klings) for details of these studies. Recently, we have also found a marked increase in erythropoietin (EPO) and expression of EPO receptors on pulmonary vascular endothelial cells that may contribute to ACS. Scleroderma: Systemic sclerosis (SSc) is characterized by autoimmunity, a small-vessel vasculopathy, and eventually fibrosis causing damage in multiple organ systems. Pulmonary hypertension (PH) is a well-described complication of SSc and occurs in 10-50% of patients depending on the study and the mode of diagnosis. The incidence of PH increases with duration of disease, with later age of onset of disease, and is greater in male patients and in patients with limited SSc. Moreover, PH is a leading cause of mortality in SSc patients and may be increasing due to longer life span of these patients. Unlike the PH that results from hypoxemia due to the parenchymal lung disease of diffuse SSc, the histology of PH associated with limited SSc is identical to other forms of PAH and is suggestive of dysregulated angiogenesis. In contrast to the evidence for excessive angiogenesis in vascular lesions of PAH, early vascular damage in SSc is characterized by EC apoptosis. In addition, serum from SSc patients contains factors such as anti-endothelial cell antibodies that not only can induce EC apoptosis but also are associated with the presence and severity of PH. These observations raise the intriguing possibility that PAH in SSc arises from an initial induction of EC apoptosis, selection of an apoptosis-resistant population of EC and the subsequent excessive angiogenesis observed in the vascular lesions of established SSc-PAH. Using genomic and proteomic technology, we are investigating the hypotheses that: 1) the vascular changes in SSc-PAH result from EC dysfunction, apoptosis and subsequent excessive angiogenesis; and 2) that specific markers of apoptosis and/or angiogenesis define distinct phenotypes in the SSc population that predict development of PAH and response to treatment. PH associated with left ventricular diastolic dysfunction: The most recent classification of PH includes a distinct category comprised of PH due to abnormalities of the left-sided cardiac chambers and valves. Left ventricular dysfunction is an important cause of PH but the existent knowledge is derived almost exclusively from patients with systolic dysfunction. However, there is growing recognition of an association between PH and the estimated 50% of heart failure patients who have, primarily, diastolic dysfunction (PH-DD); unfortunately this association has not been clearly defined, nor is it well-understood. The specific mechanisms that lead to elevated pulmonary vascular pressure in the setting of abnormal left ventricular diastolic function have not been elucidated and may go beyond a mere “reactive” phenomenon. In addition, therapeutic options are limited and target the underlying diastolic dysfunction; therapies employed in other forms of PH, specifically pulmonary arterial hypertension, such as prostaglandins, endothelin receptor antagonists, and phosphodiesterase inhibitors have not been systematically examined. We have initiated studies examining the genomic profile of patients with pulmonary hypertension associated with diastolic dysfunction (comparing them to the profile of patients with PAH and to patients with diastolic dysfunction alone). Hypoxia: Endothelial cells (EC) are remarkably hypoxia-tolerant. We have discovered and are investigating further: 1) plasmalogens, a unique antioxidant subclass of phospholipids that seemingly contribute to EC hypoxia tolerance; and 2) a specific and unique set of EC stress proteins, termed hypoxia associated proteins (HAPs). We have characterized the production and turnover of plasmalogens and have found that human EC are the only cell type in which these phospholipids can be increased above baseline. We have found that they protect EC not only from exposure to hypoxia but also from exposure to any stress associated with an increase in reactive oxygen species. We have identified all four HAPs, determined their EC and stress specificity, explored their functions and regulation and have demonstrated their existence both ex vivo and in vivo. Adiponectin: We have begun investigating the adiponectin knockout mouse as a model of pulmonary hypertension (associated with inflammation). Studies to this point have demonstrated multiple parameters of pulmonary hypertension in these mice, including elevated right ventricular pressures. Further studies are underway to define the phenotype of this mouse and determine the molecules of importance in the development of pulmonary hypertension in this mouse. Current research projects:
Principal Investigators: Harrison W. Farber Elizabeth S. Klings Surinder Safaya Flora Sam Robert Lafyatis Robert Simms Ross Summers Andy Zoeller Links:
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