Uterine Artery Structural and Functional Changes During Pregnancy in Tissue Kallikrein–Deficient Mice

Abstract

Objective-Tissue kallikrein (TK) participates in acute flow-induced dilatation (FID) of large arteries. We investigated whether TK deficiency blunts FID and alters chronic flow-related arterial structural and functional changes in resistance-sized muscular arteries. Methods and Results-Vasomotor responses and structural parameters were determined in uterine arteries isolated from nonpregnant, 18-to 19-day pregnant, and 7-day postpartum TK Ϫ/Ϫ and TK ϩ/ϩ littermate mice. In TK Ϫ/Ϫ mice, values of diameter, medial cross-sectional area (CSA), myogenic tone, and dilatation in response to acetylcholine were comparable to those values in TK ϩ/ϩ mice, but FID (0 to 100 L/min) was significantly reduced (55Ϯ4% versus 85Ϯ4% in TK ϩ/ϩ mice). In both mouse strains, pregnancy resulted in significant increases in diameter and medial CSA and in the N w -nitro-L-arginine methyl ester-sensitive component of FID. By 7 days after pregnancy, uterine arterial diameter and CSA values no longer differed from nonpregnant values, and FID was markedly reduced in TK Ϫ/Ϫ and TK ϩ/ϩ mice. Conclusions-These observations (1) confirm at the level of resistance arteries the key role of TK in FID and (2) Pressure and flow are hemodynamic determinants of circumferential wall stress and wall shear stress (WSS) in the arterial system. On an acute basis, they modulate arterial smooth muscle tone: an increase in transmural pressure triggers a myogenic contractile response, 6 -8 whereas an increase in flow induces an endothelium-dependent FID. 8 -11 Long-term changes in blood flow lead to arterial structural adaptations to normalize WSS. [12][13][14][15][16][17] In general, chronic blood flow elevations lead to a widening of lumen diameter, whereas sustained reductions in blood flow lead to a narrowing of lumen diameter. These structural arterial adaptations have been shown to be endothelium dependent. 18 Pregnancy may be considered a model of physiological flow-related remodeling of uterine arteries. It has previously been studied in rats, 19 guinea pigs, 20 and ewes. 21 During pregnancy, blood flow through the uterine circulation increases substantially. 22,23 To accommodate this increase in uterine blood flow, the uterine vasculature undergoes luminal expansion and an increase in wall mass, 19 a process termed outward hypertrophic remodeling or arteriogenesis. The driving force for this remodeling is increased WSS. Previous studies have demonstrated that chronic elevations in blood flow lead to an upregulation of FID, which is mainly due to an enhanced production of endothelial factors, such as NO and prostaglandins.The purpose of the present study was to investigate whether TK deficiency alters FID and chronic flow-related arterial structural and functional alterations in resistance-sized muscular arteries. Vasomotor responses and structural parameters were determined in uterine arteries isolated from nonpregnant, latepregnant, and postpartum TK Ϫ/Ϫ and TK ϩ/ϩ mice. Methods Mice Lacking TKTK-null mice were obtained by targeted disruption of the...

Impact of Immune Deficiency on Remodeling of Maternal Resistance Vasculature 4 Weeks Postpartum in Mice

“…In mice, an increase in the lumen diameters of mesenteric arteries was observed only in the PP period, and this was hypothesized to be related to elevated mesenteric blood flow. 12 In our study, we found a residual increased distensibility in the maternal mesenteric arteries of normal mice at 4 weeks PP but not in vessels from immunodeficient mice. Arterial compliance is controlled by multiple mechanisms, including arterial wall collagen-elastin composition, smooth muscle cell plasticity, and may involve molecules such as relaxin, 76 matrix metalloproteinases, 64 sex steroids, 77 fibulin, 78 angiotensin, and NO, among others.…”

Developmental changes in hemodynamics of uterine artery, utero- and umbilicoplacental, and vitelline circulations in mouse throughout gestation

“…The characteristics of the uterine artery waveform in the mouse were similar to that of the human, despite their much higher heart rate (ϳ500 beats/min in mice vs. ϳ75 beats/min in humans) and their much smaller uterine artery diameter (0.46 mm in mice vs. 3.4 mm in humans) (23,43). In both species, the nonpregnant uterine artery waveform has a prominent diastolic notch and a high resistance index of 0.7, although the peak systolic velocity of 23 cm/s in the mouse tends to be lower than the 32 cm/s velocity observed in humans (Table 1).…”

Toward functional genomics of flow-induced outward remodeling of resistance arteries

“…Local arteriolar and ascending vasodilatation results in an increased blood flow through the upstream resistance arteries. The resulting increase in wall shear stress triggers release of endothelium-derived vasodilators, such as nitric oxide (NO), prostacyclin, bradykinin, and endothelium-derived hyperpolarizing factor (22,24). The increase in luminal diameter tends to restore wall shear stress and leads, together with the increase in transmural pressure, to an elevation of circumferential wall stress and of the strain on the resistance arterial smooth muscle cells (SMC).…”

“…Angiogenesis, estrogeninduced upregulation of endothelial NOS, vasodilatation, and remodeling of spiral arteries and uterine arteries contribute to the increased blood flow to the growing uterus and fetuses (5). The luminal diameter and media mass of uterine arteries increase markedly in pregnant mice (22,23). This increase is accompanied by dedifferentiation of the SMC (19).…”

“…After pregnancy, most of the uterine arterial structural changes are rapidly reversed (23). Maternal deficiency in key modulators of endothelium-dependent flow-induced vasodilatation, such as tissue angiotensin-converting enzyme, tissue kallikrein, and endothelial NOS, has only limited consequences for uterine artery remodeling, fetal growth, and litter size (18,22,23). Yet, in middle-aged mice, in which flow-induced vasodilatation reaches an amplitude similar to that in young mice, uterine artery remodeling and fetal survival are simultaneously reduced (19).…”