Abnormal Myocardial and Coronary Vasculature Development in Experimental Hypoxia

Abstract

Oxygen availability is one of the necessary prerequisites for normal embryonic development. In our previous study we found that quail embryos incubated under hypoxic conditions (16% O 2 ) die at embryonic day (ED) 9 with signs of heart failure. By ED4 and ED6 we found thinner ventricular wall and increased capillary density. We thus hypothesized that the cause of death would lie in severe myocardial and coronary maldevelopment. ED6 and 7 hypoxic hearts had thinner ventricular wall, especially left. There was a simultaneous increase in capillary density, most pronounced in the interventricular septum. This site corresponds to an area of tissue hypoxia and ensuing increased angiogenesis, and also formation of ventricular conduction system. Hypoxia had a positive effect on normal sequence of maturation of the conduction system evaluated by optical mapping at ED7. In sections from ED9 hypoxic hearts we found, in addition to thinner ventricular walls, irregularities in development of coronary tree (missing coronary ostia, absence of one coronary artery, and irregular arterial wall). This deficiency was due to decreased myocyte proliferation rather than to increased apoptosis. By Indian ink injection through the left ventricle we found in normoxic hearts regular coronary branching pattern, while in the hypoxic ones there was often only an irregular plexus. Embryonic hypoxia thus leads to increased capillarity and trabeculation to minimize diffusion distance. In the subsequent period there is a failure in organization of vascular plexus into normal vasculature, resulting in thin compact myocardium that likely leads to heart failure and embryonic death.

Developmental determinants of cardiac sensitivity to hypoxia

“…Experimental studies have demonstrated that reduced fetal oxygen supply causes incomplete development of the heart, like ventricular septal defects, myocardial thinning, ventricular dilatation, and epicardium detachment, and slows fetal heart maturation (Sharma et al 2006;Ream et al 2008;Nanka et al 2008). In fetal sheep, long-term hypoxemia (natural altitude 3820 m a.s.l., 110 days) reduced cardiac output and contractility (Gilbert 1998), increased lactate dehydrogenase and citrate synthase (Ohtsuka and Gilbert 1995), and resulted in cardiomegaly (Murotsuki et al 1997;Martin et al 1998).…”

Changes in vitelline and utero-placental hemodynamics: implications for cardiovascular development

“…Effects of hypoxia on heart development were more directly addressed in quail embryos incubated under hypoxic conditions (16% oxygen) (Nanka et al, 2008). Their studies demonstrated thin ventricular walls developed and irregularities were observed in the development of the coronary tree.…”

Connecting the coronaries: How the coronary plexus develops and is functionalized

“…The base of the aorta expresses the hypoxia-induced transcription factor Hif1α, whose expression in chick is induced in response to hypoxia and correlates with coronary ostium placement (Wikenheiser et al, 2009). Exposing quail embryos to hypoxia increases the capillary density throughout the myocardium, consistent with low oxygen levels promoting vascular growth (Nanka et al, 2008). When quail embryos are placed in a hypoxic environment at approximately Hamburger-Hamilton stage 12 (after 48 h of incubation), atretic coronary arteries are observed (Nanka et al, 2008).…”

“…Exposing quail embryos to hypoxia increases the capillary density throughout the myocardium, consistent with low oxygen levels promoting vascular growth (Nanka et al, 2008). When quail embryos are placed in a hypoxic environment at approximately Hamburger-Hamilton stage 12 (after 48 h of incubation), atretic coronary arteries are observed (Nanka et al, 2008). In contrast, exposing chick embryos to either hypoxic or hyperoxic conditions starting at Hamburger-Hamilton stage 25 (or approximately 4.5–5 days of incubation) does not cause coronary atresia but does lead to both anomalous origins of the coronary stems and additional stems (Wikenheiser et al, 2009).…”

“…Indeed, most of our knowledge concerning the connection between the coronary plexus and aorta is due to observations made in chick and quail. Based on these studies, coronary stem formation begins with a fine network of vessels connecting to the aorta (Bogers et al, 1988; Bogers et al, 1989; Waldo et al, 1990; Poelmann et al, 1993; Ando et al, 2004; Nanka et al, 2008; Tomanek et al, 2008). These vessels then coalesce to form two distinct ostia.…”