Research

The brain endothelial cells (BECs) comprise the major element of the brain vasculature and a key cellular component of the blood-brain barrier (BBB). Therefore, BECs are considered the first physical barrier of defense and the gatekeeper of the central nervous system (CNS). We are interested in understanding the coordinated genetic programs that underline the unique brain endothelial phenotype and function and how these genetic programs are altered in disorders that affect the CNS.

We are studying cerebral cavernous malformations (CCMs), a disease that affects the barrier properties of the brain vasculature. CCMs are prone to repetitive hemorrhagic stroke which cause neurological deficits and occasionally death in ~0.5% of the population. Currently, no pharmacologic therapy exists for CCMs. CCMs are associated with sporadic and hereditary loss of function mutations in the genes KRIT1 (CCM1), CCM2 (Malcavernin) or PDCD10 (CCM3). The loss of endothelial function of CCM genes includes vascular dysplasia and abnormal angiogenesis. However, the molecular and cellular mechanisms implicated in the development of CCMs are not completely understood.    

To elucidate the pathogenesis of CCMs, we have performed genome-wide transcriptome analysis of BECs after acute Krit1 inactivation, and describe a signature of mRNA changes primarily affecting genes involved in cardiovascular development. Most notable was the dramatic suppression of thrombospondin1, TSP1, a potent endogenous angiogenesis inhibitor. We found that suppression of TSP1 is seen in human CCM due to the upregulation of KLF2- and KLF4 transcription factors. Using genetically engineered mice, we demonstrated that TSP1 expression contributes to the pathogenesis of CCM because inactivation of one or two copies of TSP1 gene exacerbated CCM formation. We also found that TSP1 replacement prevents development of CCM lesions in a mouse model of CCM. Our study suggested that TSP1 derivatives or other angiogenesis inhibitors may constitute a novel strategy to treat CCMs.

Grants:
  • NHLBI/NIH K01 Award