Abstract
ObjectiveAortic valve disease is a complex process characterized by valve interstitial cell activation, disruption of the extracellular matrix culminating in valve mineralization occurring over many years. We explored the function of the retinoblastoma protein (pRb) in aortic valve disease, given its critical role in mesenchymal cell differentiation including bone development and mineralization.Approach and resultsWe generated a mouse model of conditional pRb knockout (cKO) in the aortic valve regulated by Tie2-Cre-mediated excision of floxed RB1 alleles. Aged pRb cKO animals showed significantly more aortic valve regurgitation by echocardiography compared to pRb het control animals. The pRb cKO aortic valves had increased leaflet thickness without increased cellular proliferation. Histologic studies demonstrated intense α-SMA expression in pRb cKO leaflets associated with disorganized extracellular matrix and increased leaflet stiffness. The pRb cKO mice also showed increased circulating cytokine levels.ConclusionsOur studies demonstrate that pRb loss in the Tie2-lineage that includes aortic valve interstitial cells is sufficient to cause age-dependent aortic valve dysfunction.
Highlights
The aortic root diameters measured by B-mode echocardiography during systole in pRb conditional pRb knockout (cKO) and het animals were similar (Table 1), consistent with aortic valve regurgitation (AR) not being secondary to dilation of the aortic root
Functional aortic valve stenosis was not found in any animal during our study. pRb knockout (pRb cKO) heart weights normalized to tibia length were significantly heavier than pRb het hearts, suggesting mild left ventricular hypertrophy with preserved contractile function (Table 2)
We considered whether increased afterload might explain the AR; tail cuff blood pressures in pRb cKO and het mice were similar (Table 2)
Summary
There is an important need to determine the molecular mechanisms contributing to aortic valve disease because the only treatment for advanced disease is surgical replacement [3] as medical therapy has not been found effective at slowing disease progression [4, 5]. The valve interstitial cells (VICs) predominantly have an endothelial origin, [9] likely the result of endothelial-to-mesenchymal transformation of endocardial cells. Further supporting an endothelial origin of VICs, Tie lineage tracing studies produce strong staining of the aortic valve leaflet [8, 10, 11]. The adult AoV increasingly includes CD45-positive cells derived from the hematopoietic system [12] that would be expected to be derived from the Tie lineage [13]. VICs can become activated, and differentiate into myofibroblasts expressing alpha smooth muscle actin (α-SMA) [14]
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