Project Details
Description
Summary
Vascular remodeling is essential for artery formation during embryogenesis and in the
pathogenesis of vascular diseases such as atherosclerosis, restenosis, and transplant-
associated arteriosclerosis in adulthood. Despite this high clinical significance, our incomplete
understanding of the process of vascular remodeling limits current abilities to develop
preventive and therapeutic strategies. Vascular smooth muscle cells (SMCs) are main drivers of
developmental and adult vascular remodeling, but mechanisms underlying SMC activities are
not fully elucidated — in particular, the role of mitochondria and metabolism in this context is
relatively unexplored. The goal of this proposal is to understand mitochondrion-based
mechanisms that regulate SMC phenotype in vascular remodeling. We have shown that the
FAT1 cadherin interacts with and inhibits mitochondrial respiratory complex I, limits SMC
proliferation by restraining mitochondrial respiration, and opposes vascular occlusion after
arterial injury. These findings suggest that respiratory complex I regulates SMC behavior. Our
new preliminary data further support this idea. Loss of complex I subunit NDUFS4 in cultured
SMCs decreases complex I levels and activity, limits the formation of supercomplexes
containing complex I, lowers aspartate levels, and impairs cell growth. In vivo, NDUFS4 is highly
expressed during mouse development in SMCs building the arterial wall, and in adult mice in
SMC-derived cells that form the expanding neointima that accumulates in response to arterial
injury. Preliminary studies with selective NDUFS4 deletion in SMCs suggest that these cells
require respiratory complex I for normal embryogenesis. We hypothesize that complex I
promotes SMC activities important for vascular remodeling during embryogenesis and in
adulthood. We will test this hypothesis in three specific aims that respectively address the
effects of impaired respiratory complex I function 1) on key SMC activities, 2) on mouse
vascular development, and 3) in models of adult vascular homeostasis, injury, and
atherosclerotic disease. These studies will add a new respiratory complex-based angle —
susceptible to pharmacological intervention — to our understanding of how arteries form and
how they respond to injury, with relevance for tissue engineering, therapeutic angiogenesis,
tumor vascularization, and vascular disease.
Status | Finished |
---|---|
Effective start/end date | 3/1/20 → 1/31/24 |
Funding
- National Heart, Lung, and Blood Institute: $534,231.00
- National Heart, Lung, and Blood Institute: $606,879.00
- National Heart, Lung, and Blood Institute: $593,590.00
- National Heart, Lung, and Blood Institute: $536,019.00
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