Research Areas

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The main focus of our research is to understand the molecular, genetic, and cellular mechanisms underpinning the formation, function, and maintenance of the heart and blood vessels in the developing vertebrate embryo, while simultaneously understanding how these factors are dysregulated in pathological settings in the adult. We combine both zebrafish and mouse genetic models together with bioinformatics, functional genomics, and 3D imaging to investigate blood vessel development and pathogenesis. We are currently pursuing three main projects in our laboratory, as well as a long-standing interest in studying heart development. These projects are outlined below.

At the heart of these projects is a concerted effort to identity the transcriptional regulators that endow endothelium with their unique specialized identities and functional characteristics. The long-term objective of our research is to gain a deeper knowledge towards repairing or replacing damaged or diseased vessels, or alternatively preventing exuberant vascularization in disease settings, such as in glioma. To achieve this goal, a detailed mechanistic understanding of how endothelial cell identity is specified and maintained is essential.

I. Brain Arteriovenous Malformations

In 2018 our team identified somatic activating mutations within the gene KRAS in the majority of patients haboring a potentially devastating vascular anomaly: brain arteriovenous malformations (bAVMs) (see Nikolaev et. al., New Eng. J. Med, 2018). These abnormal connections between arteries and veins, which bypass the normal capillary vasculature, are extensively remodeled and quite fragile. bAVMs are the leading cause of intracranial hemorrhage in both the pediatric population and in adults under age 50. We followed up on this work showing that endothelial-specific expression of these same mutant variants drives bAVM in both zebrafish and mice (see Fish and Flores Suarez et al., Circulation Research, 2020). We are now asking if targeting this pathway can block or reverse these lesions, while also pursuing the mechanisms of KRAS-induced bAVMs at the cellular and molecular level. For more on bAVMs and the immune landscape of these lesions, see Ashely’s latest review (Ricciardelli et al., Biomedicines, 2023).

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II. Glioma & Angiogenesis in Brain Cancer

Excessive endothelial cell proliferation and sprouting are defining features of the deadly adult brain cancer, glioblastoma (GBM). Blood vessels in GBM display structural and functional heterogeneity (see Carlson and Cantu et al., Neurooncology, 2021). We are currently determining if developmental angiogenic regulators we’ve identified also regulate pathogenic angiogenesis in this setting, and whether these factors can be targeted to inhibit tumor vascularization, and thus disease progression.

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III. Creating animal Models of Human Diseases that Impact the Vasculature

The most frequently occurring class of congenital birth defects are congenital heart defects (CHDs). Our interest lies in understanding how the heart, as well as blood vessels, are patterned and develop, in terms of the myocardium, endocardium, and coronary vasculature, as well as the vascular endothelium (arteries and veins) and lymphatic endothelium. We approach this model by creating animal models (zebrafish, mice) of human diseases.

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IV. Defining the epigentic and Transcriptional Regulators of Cerebrovascular patterning and Function.

Vessels of different organs have unique properties, such as the impermeable nature of the brain endothelium (e.g. the blood brain barrier) versus the porous, fenestrated endothelium of the liver. The basis for this heterogeneity is unknown. Through transcriptional and epigenetic profiling we have identified a set of core factors present in the vessels of each major organ (see Cantu et al., biorXiv). We are now focusing on the transcription factors that govern BBB acquisition, and if these same factors can reprogram the functional characteristics of vessels in other organs.

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