Over the past decade, advances in microfabrication and biomaterials have facilitated the development of microfluidic tissue and organ models to address challenges with conventional animal and cell culture systems. These systems have largely been developed for human disease modeling and preclinical drug development and have been increasingly used to understand cellular and molecular mechanisms, particularly in the cardiovascular system where the characteristic mechanics and architecture are difficult to recapitulate in traditional systems. Here, we review recent microfluidic approaches to model the cardiovascular system and novel insights provided by these systems. Key features of microfluidic approaches include the ability to pattern cells and extracellular matrix (ECM) at cellular length scales and the ability to use patient-derived cells. We focus the review on approaches that have leveraged these features to explore the relationship between genetic mutations and the microenvironment in cardiovascular disease progression. Additionally, we discuss limitations and benefits of the various approaches, and conclude by considering the role further advances in microfabrication technology and biochemistry techniques play in establishing microfluidic cardiovascular disease models as central tools for understanding biological mechanisms and for developing interventional strategies.

Somatic activating mutations of PIK3CA are associated with development of vascular malformations (VMs). Here, we describe a microfluidic model of PIK3CA -driven VMs consisting of human umbilical vein endothelial cells expressing PIK3CA activating mutations embedded in three-dimensional hydrogels. We observed enlarged, irregular vessel phenotypes and the formation of cyst-like structures consistent with clinical signatures and not previously observed in cell culture models. Pathologic morphologies occurred concomitant with up-regulation of Rac1/p21-activated kinase (PAK), mitogen-activated protein kinase cascades (MEK/ERK), and mammalian target of rapamycin (mTORC1/2) signaling networks. We observed differential effects between alpelisib, a PIK3CA inhibitor, and rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and network topology. While both were effective in preventing vessel enlargement, rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 mitigates abnormal growth and vascular dilation. Collectively, these findings demonstrate an in vitro platform for VMs and establish a role of dysregulated Rac1/PAK and mTORC1/2 signaling in PIK3CA -driven VMs.

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