Altered hypoxia‐inducible factor‐1 alpha expression levels correlate with coronary vessel anomalies

Abstract

The outflow tract myocardium and other regions corresponding to the location of the major coronary vessels of the developing chicken heart, display a high level of hypoxia as assessed by the hypoxia indicator EF5. The EF5 positive tissues were also specifically positive for nuclear-localized hypoxia inducible factor-1 alpha (HIF-1α), the oxygen-sensitive component of the hypoxia inducible factor-1 (HIF-1) heterodimer. This led to our hypothesis that there is a “template” of hypoxic tissue that determines the stereotyped pattern of the major coronary vessels. In this study we disturbed this template by altering ambient oxygen levels (hypoxia 15%; hyperoxia 75-40%) during the early phases of avian coronary vessel development, in order to alter tissue hypoxia, HIF-1α protein expression and its downstream target genes without high mortality. We also altered HIF-1α gene expression in the embryonic outflow tract cardiomyocytes by injecting an adenovirus containing a constitutively active form of HIF-1α (AdCA5). We assayed for coronary anomalies using anti-alpha-smooth muscle actin immunohistology. When incubated under abnormal oxygen levels or injected with a low titer of the AdCA5, coronary arteries displayed deviations from their normal proximal connections to the aorta. These deviations were similar to known clinical anomalies of coronary arteries. These findings indicated that developing coronary vessels may be subject to a level of regulation that is dependent on differential oxygen levels within cardiac tissues and subsequent HIF-1 regulation of gene expression.

Cardiac Vasculature: Development and Pathology

“…Anomalies in the proximal arteries resembling those observed in clinical specimens have been reproduced in avian embryos subjected to conditions that would alter this hypoxic template (Fig 2). ; (Wikenheiser et al, 2009). Much less attention has been paid to anomalies of the cardiac veins and lymphatics.…”

“…We could not conclude the cell type requirement for HIF-1a and Cited2 using these global Cited2 and HIF-1 knockout mice, Hypoxic and hyperoxic conditions during embryogenesis alter coronary artery architecture. Regimens of hypoxia (15% O2) and hyperoxia compatible with long-term embryo survival caused coronary artery anomalies in chicken embryos (Wikenheiser et al, 2009) (Fig. 3,4).…”

“…Ao = aorta, Pt =pulmonary trunk, RC = right coronary, LC = left coronary. [From (Wikenheiser et al, 2009)] www.intechopen.com Fig. 4.…”

Gene expression profiling of changes induced by maternal diabetes in the embryonic heart

“…The altered expression of Pdgfra, Vegfa, and Tgfbr1 suggest abnormal EMTs and consequently, the formation of heart defects. Additionally, modified HIF-1␣ expression levels in the heart disrupt EMT and normal patterning of coronary vessels [60,61]. Our data document that maternal diabetes affects the temporal expression pattern of genes encoding molecules involved in endocardial and epicardial EMTs, myocardial differentiation and remodelling.…”

The <i>HIF1A</i> C85T Single Nucleotide Polymorphism Influences the Number of Branches of the Human Coronary Tree

“…Altered expression of this protein induces coronary vessel anomalies such as deviations from the normal proximal connections to the aorta, similar to clinical anomalies of coronary arteries. Overactive HIF-1 results in extra coronary arteries and attachments, some in ectopic sites [4]. Mouse embryos lacking HIF-1α expression have greatly disturbed vascularization of the embryonic yolk sac, with no organized branching vasculature [5].…”