Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disease caused by a mutation in the nuclear structural protein Lamin A. HGPS children exhibit similar phenotypes as aged individuals, including a stiffening of the large elastic arteries. Increased arterial stiffness is correlated with increased risk of cardiovascular disease, and HGPS children die in their early teens due to heart attack and stroke, likely induced by large atherosclerotic lesions. However, the mechanisms initiating and promoting arterial stiffness in HGPS are not well characterized. Vascular smooth muscle cells (VSMCs) reside in the media layer of the arteries and exist along a phenotypic spectrum from contractile (differentiated) to synthetic, matrix producing cells (dedifferentiated). Arterial stiffening is characterized by increased extracellular matrix deposition by the VSMC population, including enhanced deposition of collagen-I and crosslinking of collagens through Lysyl Oxidase (LOX). The proposed study will seek to identify the contribution of VSMC differentiation state to arterial stiffening in HGPS. Using a well-established HGPS mouse model, I will first compare differentiation state between Wild- type and HGPS VSMCs. Then, I will assess the contribution of YAP signaling, a pathway shown to regulate both VSMC differentiation state and collagen production, to arterial stiffening in HGPS. Finally, I will assess how inhibition of collagen-I cross-linking by LOX contributes to arterial stiffening. Hypothesis: I hypothesize that HGPS vascular smooth muscle cells exist in a more synthetic state and produce higher levels of collagen-I and LOX, which contribute to increased arterial stiffness. I hypothesize that a decrease in collagen-I deposition or cross-linking can alleviate arterial stiffness in HGPS.
Aim 1 : Characterize the differentiation state of VSMCs in vivo and identify YAP signaling as a potential mechanism for enhanced collagen-I production.
Aim 2 : Characterize the contribution of collagen-I crosslinking by LOX to arterial stiffness in HGPS using pharmacologic LOX inhibitor ?-aminopropionitrile.
This study will attempt to understand the causes of arterial stiffening in Hutchinson-Gilford Progeria Syndrome, an accelerating aging disease in which children die in their early teens due to cardiovascular complications such as heart attack and stroke. Understanding and targeting new methods to decrease arterial stiffening in these patients may prove a useful therapeutic approach to prolong lifespan.
