Aleksandra Babicheva
Assistant Professor

Pulmonary Vascular Diseases section studies the molecular and cellular mechanisms of pulmonary vascular disease, including pulmonary arterial hypertension (PAH). PAH is a progressive and fatal disease in which functional and structural changes in the pulmonary vasculature lead to the increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). Patients with PAH die mainly because of progressive right heart failure due to elevated PVR and PAP. Understanding normal physiological as well as cellular and molecular principles of the pulmonary circulation is a key to recognizing the abnormalities that characterize PAH and other forms of pulmonary hypertension (PH). Pathogenic features involved in PAH include sustained vasoconstriction, pulmonary vascular remodeling, in situ thrombosis, and increased vascular wall stiffness. Pulmonary vascular remodeling is characterized by significant intimal and medial hypertrophy due to i) increased proliferation of lung vascular endothelial cells (LVEC), pulmonary arterial smooth muscle cells (PASMC) and fibroblasts (FB), and ii) increased endothelial-to-mesenchymal transition (EndMT) that converts LVEC to highly proliferative myofibroblasts (myoFB). While enhanced proliferation of PASMC (and FB) mainly contribute to the concentric arterial wall thickening, increased transition of LVEC to myoFB via EndMT may contribute to the formation of intraluminal occlusion and plexiform lesions. These structural changes directly affect PVR and PAP in humans and animals with PH. The numerous cellular and molecular mechanisms have been demonstrated to contribute to these pathogenic features, often involving complex interactions. Despite the progress in our elucidation of the etiology and pathogenesis of PAH over the two last decades, there is a lack of effective therapeutic agents to treat PAH patients representing a significant unmet clinical need.

Our aim is to advance the wet-lab research concepts to translatable approaches using combined molecular biological and physiological techniques to study pathogenic mechanisms of PAH, which may result in developing more novel targets and treatment strategies for patients. We utilize rodent models of PH (hypoxia-induced PH, hypoxia/sugen5416-induced PH, monocrotaline-induced PH), pulmonary vascular cells isolated from humans and animals with PH, fluorescence Ca2+ imaging, physiological, cellular and molecular biological experiments. Research program is currently focused on:

  1. microRNA-mediated regulation of potassium channels in pulmonary vascular remodeling,
  2. role of endothelial-to-mesenchymal transition (EndMT) in PH,
  3. Ca2+ signaling and homeostasis in PASMC and LVEC.


We are trying to understand why expression and/or activity of voltage-dependent potassium (KV) channels are decreased in PASMC isolated from patients with idiopathic PAH (IPAH). A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt), plays a critical role in eliciting pulmonary vasoconstriction and stimulating PASMC proliferation. Reduced K+ channel expression and function has been shown to open voltage-dependent Ca2+ channels (VDCC), enhance Ca2+ influx and increase [Ca2+]cyt contributing to the elevated PASMC proliferation. We identified that upregulated microRNA-29b inhibited the function of the specific K+ channels via downregulation of their expression and activity in PASMC isolated from IPAH patients. Thus, significantly reduced whole cell K+ currents by miR-29b would subsequently cause membrane depolarization, enhance Ca2+ influx through VDCC, increase [Ca2+]cyt and eventually cause pulmonary vasoconstriction and pulmonary vascular remodeling (by stimulating PASMC proliferation and migration). Furthermore, decreased K+ currents or K+ efflux through KV channels in IPAH-PASMC would also inhibit PASMC apoptosis by attenuating apoptotic volume decrease and inhibiting cytoplasmic caspase activity and further contribute to pulmonary vascular remodeling.

LVEC play a major role in maintaining low arterial resistance and pressure by releasing vasodilative and hyperpolarizing factors. LVEC also proliferate much slowly in response to growth factors compared to PASMC and FB. EndMT has recently been implicated in severe forms of PAH by phenotypically converting slowly growing functional LVEC to highly proliferative myoFB and enabling LVEC to contribute to the development of pulmonary vascular remodeling involving occlusive and plexiform intimal lesions. We aim to reveal the mechanisms driving EndMT in the development and progression of PH. We demonstrated that EndMT contributed to the severe pulmonary vascular remodeling and the formation of obliterative lesions in humans and animals with PH. Moreover, endothelial hypoxia-inducible factor-2α (HIF-2α) signaling is involved in EndMT by positively regulating transcription factors SNAI1/2. Deletion of the negative regulator of endothelial HIF-2α, prolyl hydroxylase domain 2 (Phd2), resulted in the activation of HIF-2α signaling, development of EndMT, pulmonary vascular remodeling and spontaneous PH in mice. Given the fact that Ca2+ is a critical mediator for a phenotypical transition in cells we are investigating whether Ca2+ signaling is involved in EndMT during PH. By using transforming growth factor β1 (TGF-β1)-induced EndMT as in vitro model we revealed that extracellular Ca2+ is required for stimulation of transcription factors SNAI1/2 and promotion of EndMT.

We currently have openings for highly motivated students, postdoctoral fellows and visiting scholars with keen interest to pursue research in pulmonary vascular diseases. Please send your CV to Dr. Babicheva for further consideration.