NIH grant: Mechanisms of Vascular Dysfunction in Down Syndrome (1R21HL184091-01)

retained text

NIH grant 1R21HL184091-01: Mechanisms of Vascular Dysfunction in Down Syndrome
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: DANIEL Robert MACHIN. Award: $419375.
Start: 2026-07-01T00:00:00.
PROJECT SUMMARY
 Down syndrome (DS) results from the triplication of human chromosome 21 (HSA21). In addition to congenital
heart disease, which affects ~50% of the DS population, there are numerous other vascular abnormalities in DS,
such as low systolic blood pressure (BP) and low aortic stiffness that are paradoxically accompanied by
endothelial dysfunction. Cardiovascular disease (CVD) is the leading cause of death with advancing age in DS.
While the underlying mechanisms of CVD risk in DS are unknown and understudied, endothelial dysfunction
likely plays a major role. Our preliminary findings suggest 4 mo old TcMAC21 mice, a mouse model of DS, have
a similar arterial phenotype to people with DS, with lower systolic BP and aortic stiffness compared to euploid
littermates. TcMAC21 mice also have endothelial dysfunction that is accompanied by a depleted endothelial
glycocalyx. The endothelial glycocalyx is a network of glycosaminoglycans attached to the endothelium that
protects endothelial cells (ECs) from blood borne factors, such as oxidants and inflammatory cytokines. There
is emerging evidence that endothelial dysfunction may be initiated by a dysfunctional glycocalyx. Our
observations of a depleted glycocalyx in TcMAC21 mice are the only evidence in any model of DS, as no other
studies have investigated any aspect of the glycocalyx in human or animal models of DS. In addition to abnormal
vascular physiology, people with DS have elevated oxidative stress and inflammation. In the general population,
endothelial dysfunction results from oxidative stress and inflammation that lower nitric oxide (NO) bioavailability
and is accompanied by impaired endothelial cell (EC) autophagy that promotes cellular senescence. People with
DS exhibit accelerated aging, and impaired autophagy and premature cellular senescence have been shown in
fibroblasts from human donors with DS. However, it is unknown if this occurs in ECs. It is possible that endothelial
dysfunction, impaired autophagy, and premature senescence in DS are caused by amyloid-β (Aβ)
pathophysiology, as the amyloid precursor protein (APP) gene is located on HSA21. Thus, people with DS
overexpress APP and produce more Aβ. In DS, Aβ is often linked to early-onset Alzheimer’s disease, but excess
Aβ may also impair endothelial function via oxidative stress and inflammation, which ultimately contributes to
CVD. Currently, it is unknown if excess Aβ degrades the glycocalyx. The proposed studies will test the central
hypothesis that excess Aβ production in DS leads to glycocalyx depletion, endothelial dysfunction, impaired
autophagy, and cellular. The successful completion of the proposed studies will determine if elevated Aβ in DS
is a risk factor for accelerated aging of the cardiovascular system and will determine specific targets that mediate
this effect to provide potential targeted therapies for personalized treatment of CVD in people with DS and other
conditions with increased Aβ.

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