Dr. Yang Xia, Associate Professor

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molecular basis of cardiovascular diseases

The focus of my laboratory is to identify the signaling pathways that control the pathophysiology of cardiovascular diseases.  Two projects are currently under investigation in my lab.

I. Angiotensin receptor autoantibodies and the pathophysiology role in preeclampsia:
Preeclampsia is characterized by hypertension, proteinuria and endothelial dysfunction.  The condition affects approximately 5% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity in the United States and the world.  The clinical management of preeclampsia is hampered by the lack of pre-symptomatic screening, reliable diagnostic tests and effective therapy. 

Recent studies from our laboratory indicate that the persistent presence of angiotensin AT1 receptor agonistic autoantibodies (herein termed AT1-AA) are a risk factor for the onset and development of preeclampsia. We have recently shown that key features of preeclampsia, including hypertension, proteinuria, placental abnormalities (including increased secretion of anti-angiogenic factors) and small fetuses appeared in pregnant mice following injection with either total IgG or affinity purified AT1-AA from women with preeclampsia via AT1 receptor activation.  Our studies are the first to provide direct evidence that preeclampsia may be a pregnancy-induced autoimmune disease in which key features of the disease result from AT1-AA (Fig.1). Therefore, our long-range goal is to evaluate the molecular basis of AT1-AA in preeclampsia, explore the immunological origins of these autoantibodies and develop a novel diagnostic and therapeutic possibility for the disease. We are well poised to use multiple techniques including biochemistry, molecular, cellular systems, in vivo animal, physiology and histology to experimentally address these issues.


Fig.1 AT1-AA induces preeclampsia in pregnant mice, suggesting a novel hypothesis that preeclampsia is a gestational-induced autoimmune disease. Testing this hypothesis is the one of the major goals in my lab as proposed in this application.

II. Adenosine signaling in normal penile erection, priapism and erectile dysfunction: Normal penile erection is controlled at multiple levels: neuronal, hormonal and vascular.  The tone of vascular smooth muscle cells is a key regulator of penile erection and is determined by the balance of vascular smooth muscle relaxants and constrictors.  An imbalance of vascular regulators may lead to either erectile dysfunction due to over constriction or priapism due to over relaxation.   Both disorders are highly associated with cardiovascular diseases. Particularly, about 40% of sickle cell disease (SCD) patients display priapism.  The treatment options for priapism are poor due to lack of fundamental understanding of the pathophysiology of penile erection.

Recently my laboratory unexpectedly found that male adenosine deaminase (ADA)-deficient mice display features of priapism seen in humans, including spontaneous prolonged penile erection with subsequent penile fibrosis. In addition, we demonstrated that reducing the accumulation of adenosine by ADA enzyme therapy relieved spontaneous prolonged penile erection, an observation with obvious therapeutic applications. Moreover, the analysis of four adenosine receptor deficient mice revealed that the A2BR is essential for adenosine-mediated cavernosal smooth muscle relaxation (i.e. penile erection) and that up-regulated A2BR signaling contributes to priapic activity in ADA-deficient mice.  Finally we found that priapic activity in the SCD transgenic mouse, a well accepted priapic animal model, is also due to elevated adenosine signaling via A2BR, suggesting a general contributory role of adenosine and A2BR signaling in priapism.  My laboratory has acquired significant research experience in most areas of biochemistry, molecular genetics, physiology, histology and vascular biology needed to investigate the molecular mechanisms of adenosine signaling in normal and abnormal penile erection including erectile dysfunction and priapism in general.  These studies will provide the potential therapeutic possibility for the disease.

Fig. 2. Role of nitric acid (NO) and adenosine signaling in penile erection. Excess adenosine contributes to priapism in both ADA-deficient mice and SCD Tg mice (2).  This finding leads us to hypothesize that adenosine is important signaling molecules for normal and abnormal penile erection.

Selected References