We seek to identify the molecular, cellular and genetic mechanisms that regulate adaptive and neoplastic angiogenic responses. Our studies define novel molecular and cellular signaling pathways important in vascular pathogenesis. Understanding these pathways is critical to the design and development of new therapies for human cardiovascular and cancer diseases.
Filamins are large actin-binding proteins that stabilize delicate three-dimensional actin filament networks and link them to cellular membranes where they integrate cell architectural and signaling functions important for cell locomotion. Filamins have been shown to bind to proteins with diverse functions and are implicated in human genetic diseases including malformations of the skeleton, brain, and heart.
We produced mouse models of filamin deficiency and cell lines deficient for filamins that have advanced our understanding of the important roles that filamins play in embryonic development and disease progression. These studies provide clear evidence that cytoskeletal filamin proteins integrate cell signaling, transcription and organ development. We focus on the emerging roles of filamins, particularly in cell motility during cardiovascular diseases and tumor growth.
Zheng X, Zhou X, Rouhi P, Uramoto H, Borén J, Cao Y, Pereira T, Akyürek LM* and Poellinger L*. Hypoxia-induced and calpain-dependent cleavage of filamin-A regulates the hypoxic response. Proc Natl Acad Sci USA 111:2560-5 (2014)
*Equal contribution as senior authors
Nallapalli RK, M. Ibrahim X, Zhou A-X, Bandaru S, Sunkara SN, Redfors B, Pazooki D, Zhang Y, Borén J, Cao Y, Bergö MO, and Akyürek LM. Targeting filamin A efficiently reduces K-Ras‒induced lung tumor development and endothelial response to tumor growth in mice. Molecular Cancer 11:50 (2012)
Zhou AX, Hartwig JH, Akyürek LM. Filamins in cell signaling, transcription and organ development. Trends Cell Biol 20:113–23 (2010)
Zhou X, Tian F, Sandzén J, Cao R, Flaberg E, Szekely L, Cao Y, Ohlsson C, Bergö MO, Borén J, Akyürek LM. Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development. Proc Natl Acad Sci USA 104:3919–24 (2007)
Although induction of angiogenesis would appear to be an ideal therapeutic strategy, clinical trials of pro-angiogenic factors to treat cardiovascular diseases or tumors have proved disappointing. Angiogenesis is a complex process involving many signaling pathways and mediators, and further insights into the underlying cellular and molecular mechanisms are urgently needed.
We use mouse models of systemic hypoxia and myocardial infarction to study the effects of hypoxia on angiogenesis in the myocardium, and the novel cellular and molecular mechanisms involved. Our research is focused on defining the hypoxic responses in the vascular endothelium.
Bandaru S, Grönros J, Redfors B, Çil Ç, Pazooki D, Salimi R, Larsson E. Ömerovic E, Akyürek LM. Deficiency of endothelial filamin A impairs left ventricular remodeling after myocardial infarction. Cardiovasc Res 105, 1151–1159 (2015)
Tian F, Zhou AX, Smits AM, Larsson E, Goumans MJ, Heldin CH, Borén J, Akyürek LM. Endothelial cells are activated during hypoxia via endoglin/ALK-1/SMAD1/5 signaling in vivo and in vitro. Biochem Biophys Res Commun 392:283–8 (2010)
Tian F, Zhou X, Wikström J, Karlsson H, Sjöland H, Gan LM, Borén J, Akyürek LM. Protein disulfide isomerase increases in myocardial endothelial cells in mice exposed to chronic hypoxia: a stimulatory role in angiogenesis. Am J Physiol 297:H1078–86 (2009)
We receive grants primarily from the Swedish Cancer Society and Västra Götalandsregionen.
Sashidar Bandaru, PhD Fellow
Reza Salimi, Visiting PhD Fellow
Sravani Devarakonda, Undergraduate Student
Srujana Gosangi, Undergraduate Student
David Pazooki, Postdoctoral Fellow