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Updated: Apr 22, 2026
In Vitro Model of Coronary Angiogenesis
Published on: March 10, 2020
KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF)
Peter V DiStefano1, Julia M Kuebel1, Ingrid H Sarelius1
1From the Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642.
Insights
Loss of KRIT1 protein disrupts endothelial cell junctions by upregulating VEGF-A signaling. This impacts cell behavior and blood vessel permeability, though other factors also contribute to these disruptions.
Area of Science:
- Vascular Biology
- Cellular Signaling
- Cardiovascular Research
Background:
- Endothelial cell-cell contact disruption is central to cardiovascular diseases.
- The cerebral cavernous malformation (CCM) protein family (KRIT1, PDCD10, CCM2) regulates endothelial junctions and vascular homeostasis.
- Pathologically activated endothelium exhibits disrupted cell-cell contacts.
Purpose of the Study:
- To investigate the novel regulation of vascular endothelial growth factor (VEGF) signaling in KRIT1-depleted endothelial cells.
- To elucidate the role of KRIT1 in controlling VEGF-A expression and downstream signaling pathways.
- To determine the contribution of VEGF signaling to endothelial dysfunction and permeability in KRIT1 deficiency.
Main Methods:
- Utilized KRIT1-depleted endothelial cells and KRIT1-deficient animal models.
- Assessed nuclear beta-catenin signaling and VEGF-A protein expression.
- Measured VEGF receptor 2 (VEGFR2) activation, cytoskeletal organization, cell migration, and barrier function.
- Investigated in vivo endothelial permeability in KRIT1-deficient animals.
Main Results:
- Loss of KRIT1 and PDCD10, but not CCM2, increased nuclear beta-catenin signaling and VEGF-A protein expression.
- In KRIT1-depleted cells, elevated VEGF-A led to increased VEGFR2 activation, altering cytoskeletal organization, migration, and barrier function.
- KRIT1 deficiency resulted in increased in vivo endothelial permeability in KRIT1-deficient animals.
- VEGFR2 activation partially contributed to the disruption of cell-cell contacts observed in KRIT1-depleted cells.
Conclusions:
- VEGF signaling plays a significant role in modifying endothelial function and microvessel permeability in KRIT1-deficient contexts.
- While VEGF signaling contributes, it is not the sole factor responsible for the disruption of endothelial cell-cell contacts in the absence of KRIT1.
- Further research is needed to identify other contributing factors to KRIT1 deficiency-associated endothelial dysfunction.
Abstract:
Disruption of endothelial cell-cell contact is a key event in many cardiovascular diseases and a characteristic of pathologically activated vascular endothelium. The CCM (cerebral cavernous malformation) family of proteins (KRIT1 (Krev-interaction trapped 1), PDCD10, and CCM2) are critical regulators of endothelial cell-cell contact and vascular homeostasis. Here we show novel regulation of vascular endothelial growth factor (VEGF) signaling in KRIT1-depleted endothelial cells. Loss of KRIT1 and PDCD10, but not CCM2, increases nuclear β-catenin signaling and up-regulates VEGF-A protein expression. In KRIT1-depleted cells, increased VEGF-A levels led to increased VEGF receptor 2 (VEGFR2) activation and subsequent alteration of cytoskeletal organization, migration, and barrier function and to in vivo endothelial permeability in KRIT1-deficient animals. VEGFR2 activation also increases β-catenin phosphorylation but is only partially responsible for KRIT1 depletion-dependent disruption of cell-cell contacts. Thus, VEGF signaling contributes to modifying endothelial function in KRIT1-deficient cells and microvessel permeability in Krit1(+/-) mice; however, VEGF signaling is likely not the only contributor to disrupted endothelial cell-cell contacts in the absence of KRIT1.
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