Reduced vessel elasticity alters cardiovascular structure and function in newborn mice

Abstract

Elastic blood vessels provide capacitance and pulse-wave dampening, which are critically important in a pulsatile circulatory system. By studying newborn mice with reduced (Eln(+/)(-)) or no (Eln(-)(/)(-)) elastin, we determined the effects of altered vessel elasticity on cardiovascular development and function. Eln(-)(/)(-) mice die within 72 hours of birth but are viable throughout fetal development when dramatic cardiovascular structural and hemodynamic changes occur. Thus, newborn Eln(-)(/)(-) mice provide unique insight into how a closed circulatory system develops when the arteries cannot provide the elastic recoil required for normal heart function. Compared with wild type, the Eln(-)(/)(-) aorta has a smaller unloaded diameter and thicker wall because of smooth muscle cell overproliferation and has greatly reduced compliance. Arteries in Eln(-)(/)(-) mice are also tortuous with stenoses and dilations. Left ventricular pressure is 2-fold higher than wild type, and heart function is impaired. Newborn Eln(+/)(-) mice, in contrast, have normal heart function despite left ventricular pressures 25% higher than wild type. The major vessels have smaller unloaded diameters and longer lengths. The Eln(+/)(-) aorta has additional smooth muscle cell layers that appear in the adventitia at or just before birth. These results show that the major adaptive changes in cardiovascular hemodynamics and in vessel wall structure seen in the adult Eln(+/)(-) mouse are defined in late fetal development. Together, these results show that reduced elastin in mice leads to adaptive remodeling, whereas the complete lack of elastin leads to pathological remodeling and death.

Figure 1

Reduced elastin levels correlate with increased LV pressure. Representative LV pressure waveforms (a), average calculated systolic pressure (b), and average heart rates (c) for all genotypes are shown. N=5 (WT and Eln^+/−) and N=3 (Eln^−/−). *P<0.05 between all genotypes.

Figure 2

The reduced compliance of Eln^−/− ascending aorta is illustrated by representative M-mode images from the echocardiographic studies. Note the small change in inner diameter of the Eln^−/− aorta between end-systole (IDs) (mm) and end-diastole (IDd) (mm) and that all genotypes have approximately the same end-systolic diameter.

Figure 3

Elastin insufficiency alters vascular morphology. The heart (H), ductus arteriosus (D), ascending aorta (AA), right subclavian (RS), right carotid (RC), left carotid (LC), left subclavian (LS), and descending aorta (DA) are labeled in representative morphologic images (a). Eln^+/− arteries have smaller diameters, longer lengths, and a sharp bend at the RS (white arrow). Eln^−/− arteries have stenoses, dilations, and tortuosity (black arrows). The eosin dye did not flow into the Eln^−/− left carotid (LC), but the artery can be identified by blood clots in the stenosed regions (black arrowhead). Scale bars=0.5 mm. Areas 1 and 2 in the Eln^−/− image correspond to regions where the blood flow velocities were measured with Doppler ultrasound and are shown in b. Low flow (1) is present in the dilated region, and high flow (2) is present in the stenosed region (b). Scale bars=20 cm/sec.

Figure 4

Eln^+/− and Eln^−/− mice have unique vascular wall organization. Representative electron microscopic images taken at ×700 original magnification of the proximal ascending aorta in each genotype are shown. The adventitia is at the top of the images. Note the additional elastic laminae near the adventitial interface in Eln^+/− aorta and disorganized SMCs near the intimal interface in Eln^−/− aorta (black arrows). Scale bars=11 μm.

Figure 5

Eln^−/− mice have reduced aortic diameter and compliance in vitro. Average outer diameter (OD) (a) and average compliance (C) (b) vs pressure. N=10 (WT), N=12 (Eln^+/−), and N=6 (Eln^−/−). *P<0.05 for Eln^−/− compared to WT and Eln^+/−; ‡P<0.05 between WT and Eln^−/−; &P<0.05 between Eln^+/− and Eln^−/−; $P<0.05 between WT and Eln^+/−; #P<0.05 for Eln^+/− compared to WT and Eln^−/−.

Figure 6

Eln^−/− aorta has altered circumferential stresses, and Eln^+/− aorta has altered circumferential stretch ratios. Average circumferential stress (a), axial stress (b), and circumferential stretch ratio (c) vs pressure are shown. N=10 (WT), N=12 (Eln^+/−), and N=6 (Eln^−/−). @P<0.05 between all genotypes; *P<0.05 for Eln^−/− compared to WT and Eln^+/−; #P<0.05 for Eln^+/− compared to WT and Eln^−/−.