Rebuilding the coronary vasculature: hedgehog as a new candidate for pharmacologic revascularization

Abstract

Myocardial infarction and ischemic heart disease are among the most common causes of morbidity and mortality in the industrial world. Surgical and percutaneous intravascular approaches are commonly used to treat these diseases. Regrettably, a significant number of patients are either ineligible or demonstrate suboptimal responses to these therapies. In an attempt to provide such patients improved therapeutic options, much effort has been spent developing noninvasive approaches to restore coronary vascular perfusion. One such strategy, termed therapeutic revascularization or angiogenesis, involves administration of proangiogenic factors, which improve coronary perfusion by promoting growth of the coronary vasculature. Thus far, two potential proangiogenic factors have been intensively examined, fibroblast growth factor and vascular endothelial growth factor. Unfortunately, despite their apparent efficacy in animal models, neither factor has performed adequately in the clinic to date. Within the past year a new factor, hedgehog, has been shown to effectively promote the growth of the coronary vasculature and thus has been proposed as a novel candidate for therapeutic revascularization. In this review, we discuss the discovery of the hedgehog pathway as an essential regulator of the development of the coronary vasculature, as an inducer of adult coronary vascular growth, and as a therapeutic in the treatment of ischemic heart disease.

Figure 1

Development of the coronary vasculature. Platelet/endothelial cell adhesion molecule-1/CD31 immunostaining of murine embryonic day (E)11.5 to E14.5 and E16.5 hearts demonstrating the progression of coronary growth during development. Between E11.5 and E13.5, the developing coronary vasculature plexus emerges from the atrial ventricular groove (red bracket) and grows in a wavelike pattern to cover both ventricles by E13.5. Between E14.5 and E16.5, the coronary vascular plexus remodels, giving rise to the mature coronary vasculature.

Figure 2

The coronary vascular plexus consists of two subsets of blood vessels. Left and middle, H&E-stained histological sections of murine embryonic hearts showing the formation of the subepicardial mesenchyme (SEM) between E11.5 and E13.5. Right, Histological section of a PECAM-stained E13.5 heart revealing two sets of developing coronary vessels. The intramyocardial blood vessels (intramyo. BV) course through the myocardial wall, whereas the subepicardial blood vessels (subepi. BV) grow within the subepicardial mesenchyme.

Figure 3

Hedgehog signaling controls the development of the coronary vasculature. (A) Schematic highlighting the simultaneous wavelike expansion of the coronary vascular plexus and HH activation between E11.5 and E13.5. The blue-colored area denotes the expression domain of Ptc1, Vegf-A, Vegf-B, Vegf-C, and Ang2. (B) An FGF-HH-VEGF/ANG signaling cascade controls embryonic coronary development. Model depicting the spatial relationship between FGF, HH, VEGF, and ANG growth factors during coronary development. Dashed arrow and question mark represent the unidentified myocardial to epicardial signal controlling SHH expression.

Figure 4

Comparison between HH signaling during embryonic and adult coronary vascular growth. Top, Model displaying the source and target tissues of FGF, HH, VEGF, and ANG signals. Dashed arrow and question mark represent the unidentified myocardial to epicardial signal controlling SHH expression. Bottom, Model describing the mechanism by which HH signaling controls coronary growth in the adult heart. Question marks represent components proposed to be involved in this signaling cascade.