Skip to contents
Guillermo Garcia-Cardena, PhD
Scientist, Brigham and Women's Hospital
Associate Professor of Pathology, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115

Research Location: Harvard New Research Building


Edit Profile


Research Narrative:

BIOMECHANICAL CONTROL OF ENDOTHELIAL CELL IDENTITY AND FUNCTION

Our laboratory is using cellular, molecular, bioengineering, and bioinformatics tools to understand how mechanical forces generated by the flow of blood act on endothelial cells to activate signaling pathways critical for cellular specification during developmental processes, and for flow-mediated vasoprotection in the context of human cardiovascular disease.

Biomechanical Control of Embryonic Developmental Processes

When the heart starts beating and blood flow is first established during vertebrate development endothelial cells lining nascent blood vessels are first expose to hemodynamic forces. The effects that this critical developmental transition has on the developing vascular system remains poorly characterized. We are studying two processes related to this transition namely, arterial specification and the induction of embryonic hematopoiesis.
1) We have documented that the hemodynamic forces present in the arterial tree are critical for the specification and maintenance of endothelial arterial endothelial identity in vitro and in vivo. These data suggest that in addition to genetic specification hemodynamic forces act as modifiers of endothelial arterial identity.
2) Vascular haematopoietic activity has been recently shown to be the source of definitive haematopoietic progenitors and therefore of the adult haematopoietic system. While the hemogenic endothelium appears in blood vessels after the initiation of heartbeat, it was unknown whether the biomechanical forces imposed on the vascular wall could act as a determinant of haematopoietic potential. However, in collaboration with Dr. George Daley (Children’s Hopital Boston) we recently demonstrated that this is indeed the case by documenting that hemodynamic forces stimulate embryonic haematopoiesis in murine stem cell cultures and within murine embryos. These observations establish a link between the initiation of vascular flow and embryonic perivascular hematopoietic development.

Biomechanical Control of Endothelial Vasoprotection

In experiments design to probe the transcriptional machinery responsible for the endothelial vasoprotective phenotype present in regions of the human vasculature resistant to atherogenesis, we revealed that the transcription factor Kruppel-like factor 2 (KLF2) acts as an integrator of the flow-mediated endothelial vasoprotective phenotype. Importantly, we also demonstrated that Statins increase the expression of KLF2, explaining in part, the well-described non-lipid lowering, vasoprotective effects of this class of drugs. These observations have led us to initiate high-throughput screens to identify small molecules and siRNAs capable of regulating KLF2 expression. These experiments should enable us to dissect mechanistically how flow leads to the expression of KLF2, and could aid in the identification of new molecules capable of acting as “pharmacomimetics of flow-dependent vasoprotection”.

The ultimate objectives of our research program are twofold: to generate a molecular description of flow-mediated endothelial mechanotransduction in specific biological processes, in order to provide a framework for understanding how genes and hemodynamic environments dictate cell fate decisions and functional phenotypes; and to probe these molecular maps to improve diagnosis and treatment of human disease.
 


Education:
Yale University, PhD

Lab Members:
Jordi Gracia-Sancho, PhD, Postdoctoral Fellow
Luigi Adamo, MD, PhD, Postdoctoral Fellow
William Adams, Graduate Student
Andrew Koo, Graduate Student
Guadalupe Villarreal, Jr., Medical Student

Publications (Pulled from Harvard Catalyst Profiles):

1. García-Cardeña G, Slegtenhorst BR. Hemodynamic Control of Endothelial Cell Fates in Development. Annu Rev Cell Dev Biol. 2016 10 06; 32:633-648.

2. Gimbel AA, Flores E, Koo A, García-Cardeña G, Borenstein JT. Development of a biomimetic microfluidic oxygen transfer device. Lab Chip. 2016 08 16; 16(17):3227-34.

3. Gimbrone MA, García-Cardeña G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res. 2016 Feb 19; 118(4):620-36.

4. Malaspinas O, Turjman A, Ribeiro de Sousa D, Garcia-Cardena G, Raes M, Nguyen PT, Zhang Y, Courbebaisse G, Lelubre C, Zouaoui Boudjeltia K, Chopard B. A spatio-temporal model for spontaneous thrombus formation in cerebral aneurysms. J Theor Biol. 2016 Apr 07; 394:68-76.

5. Yuan L, Chan GC, Beeler D, Janes L, Spokes KC, Dharaneeswaran H, Mojiri A, Adams WJ, Sciuto T, Garcia-Cardeña G, Molema G, Kang PM, Jahroudi N, Marsden PA, Dvorak A, Regan ER, Aird WC. A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity. Nat Commun. 2016 Jan 08; 7:10160.

6. Diaz MF, Li N, Lee HJ, Adamo L, Evans SM, Willey HE, Arora N, Torisawa YS, Vickers DA, Morris SA, Naveiras O, Murthy SK, Ingber DE, Daley GQ, García-Cardeña G, Wenzel PL. Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis. J Exp Med. 2015 May 04; 212(5):665-80.

7. Tabas I, García-Cardeña G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol. 2015 Apr 13; 209(1):13-22.

8. French A, Bravery C, Smith J, Chandra A, Archibald P, Gold JD, Artzi N, Kim HW, Barker RW, Meissner A, Wu JC, Knowles JC, Williams D, García-Cardeña G, Sipp D, Oh S, Loring JF, Rao MS, Reeve B, Wall I, Carr AJ, Bure K, Stacey G, Karp JM, Snyder EY, Brindley DA. Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards. Stem Cells Transl Med. 2015 Mar; 4(3):217-23.

9. Marrone G, Maeso-Díaz R, García-Cardena G, Abraldes JG, García-Pagán JC, Bosch J, Gracia-Sancho J. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut. 2015 Sep; 64(9):1434-43.

10. Okada Y, Funahashi N, Tanaka T, Nishiyama Y, Yuan L, Shirakura K, Turjman AS, Kano Y, Naruse H, Suzuki A, Sakai M, Zhixia J, Kitajima K, Ishimoto K, Hino N, Kondoh M, Mukai Y, Nakagawa S, García-Cardeña G, Aird WC, Doi T. Endothelial cell-specific expression of roundabout 4 is regulated by differential DNA methylation of the proximal promoter. Arterioscler Thromb Vasc Biol. 2014 Jul; 34(7):1531-8.