From Bump to Pump: Extracellular Matrix Remodeling, Dynamics, and Biomechanics in the Maternal Heart

Abstract

Although a large percentage of pregnancy-related morbidity and mortality is the result of cardiovascular diseases, little is known about the underlying mechanisms that contribute to the development of adverse cardiac changes during pregnancy. It is clear that during pregnancy, the heart adapts to increased ventricular preload through the development of a reversible, pregnancy-induced cardiac hypertrophy. Cardiomyocyte growth must be supported by changes in the cardiac extracellular matrix (ECM), an extremely diverse and dynamic set of components, whose composition and regulation affect cardiac biomechanics. The ECM undergoes extensive remodeling during periods of cardiac stress, such as those experienced during pregnancy and the postpartum period; however, the full extent of ECM changes and their contributions to biomechanical changes and maternal heart plasticity remain vastly understudied. Recent studies suggest alterations in the expression of several fibrillar collagens, such as collagens I and III, and regulatory proteins, such as matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases, occur during a healthy pregnancy. On the contrary, in the setting of pregnancy-associated cardiovascular diseases, such as preeclampsia and peripartum cardiomyopathy, adverse changes in ECM remodeling have been reported. This review aims to summarize the current state of the field highlighting changes in the cardiac ECM and its components during healthy pregnancies, how perturbations in ECM remodeling can lead to the development of pregnancy-related cardiovascular pathologies, and discuss the notable gaps in knowledge that need to be addressed if we are to fully understand ventricular remodeling in the context of pregnancy and reduce maternal cardiovascular disease burden.

Introduction

During pregnancy, the heart rapidly adapts to the increased preload imposed by elevated blood volume. One such adaptation is the development of pregnancy-induced cardiac hypertrophy(1), which helps meet maternal-fetal circulatory needs. Pregnancy-induced cardiac hypertrophy is believed to be transient, because the heart is thought to return to a pre-pregnancy-like size following parturition, when blood volume returns back to pre-pregnancy levels(1–5). This regression does not occur in instances of pathological remodeling(4). These periods of cardiac growth and regression likely require the female heart to possess a degree of plasticity and likely require careful coordination between the contractile cells (i.e., cardiomyocytes) and the surrounding extracellular matrix (ECM). Although the development of pregnancy-induced cardiac hypertrophy has been documented in several models(1–5), much less is known about the underlying mechanisms that contribute to maternal cardiac plasticity, and the nature of the coordination between cardiac cellular compartments that facilitate growth and reversion.

Changes in the ECM occur during instances of both physiological and pathological cardiovascular remodeling. For example, the cardiac ECM changes significantly over the course of a healthy pregnancy, such that periods of heightened cardiac growth are associated with dynamic changes in the ECM transcriptome(2, 5–7). Conversely, pathological remodeling, such as that seen after myocardial infarction or with cardiomyopathy, will also result in heightened cardiac remodeling, but is often associated with excessive collagen deposition(8). This fibrotic response is not only irreversible but also adversely impacts ventricular compliance and resultant function. A stark difference between these two types of remodeling is that pregnancy-induced cardiac remodeling is not associated with bulk collagen deposition or functional decrements(2–5). Emerging evidence does suggest, however, that pregnancy-associated cardiovascular diseases, such as pre-eclampsia and peripartum cardiomyopathy, are associated with adverse changes in the structure of the ECM(9–11). Recent evidence also suggests that lifelong alterations in the cardiovascular system occur as a result of cardiovascular complications during pregnancy (12). Despite this, little is known regarding the mechanisms that precipitate adverse matrix remodeling in the context of these pregnancy-associated cardiovascular diseases. This is important to know because understanding the contributing factors that trigger adverse ECM remodeling during pregnancy could help to identify pathways and processes that can be targeted to prevent the transition from dynamic to irreversible remodeling in the maternal heart. In addition, with the steady increase in maternal mortality rates precipitated by cardiovascular disease burden(13), having an abundance of knowledge of the remodeling processes that occur in the maternal heart could eventually help to reduce adverse outcomes. Therefore, the goal of this review is to discuss the current state of the field regarding maternal cardiac ECM remodeling and the biomechanical properties of the matrix in both healthy and cardiovascular disease-complicated pregnancies. We will specifically highlight key proteins and signaling pathways that contribute to pregnancy-associated changes in matrix remodeling, highlight the remaining major knowledge gaps, and highlight key areas for future mechanistic investigations that will contribute to the advancement of our current understanding of pregnancy-associated changes in the matrix.

Cardiac ECM and Biomechanical Functions

The cardiac ECM is dynamic and diverse, made up of many different types of proteins. The composition of the ECM is tissue-specific, such that the makeup of the cardiac ECM is different than the ECM composition of other tissues. The cardiac ECM is composed of the basement membrane and the interstitial matrix, in addition to proteoglycans and associated glycosaminoglycans. The basement membrane is mainly composed of type IV collagens, laminins, and nidogens, and it forms a scaffold that interacts with growth factors and integrins, making it an important site of cell-matrix interactions(14). While basement membrane components, such as Col4a1, Col4a2, and Col15a1, have been shown to contribute to certain cardiac pathologies(14), the biomechanical properties and functions of the basement membrane have been severely understudied as a result of increased focus on the interstitial matrix.

The interstitial matrix is composed of fibrillar collagens (i.e., type I and type III collagens), elastin, fibronectins, and proteoglycans. Cardiac fibroblasts, which secrete many of the components that make up the ECM, are also interspersed throughout the interstitial matrix(15). The makeup of the cardiac interstitial matrix, as well as the basement membrane and its components under healthy and diseased conditions, are shown in Figure 1. These components afford the mechanical properties of the cardiac ECM, house growth factors, and contribute to molecular pathways that are essential to cardiomyocyte function and will now be discussed in greater detail.

Figure 1. The Structure of Healthy and Diseased Cardiac ECM.

This depicts simplified structures of the basement membrane (BM) and interstitial matrix (IM) during healthy (A) and disease states (B). The disease state depicted reflects non-ischemic cardiovascular disease where interstitial fibrosis is common. Figure key (inset) describes the components, which include laminin, collagens, proteoglycans, fibronectin, and cardiac fibroblasts. This Figure was created in BioRender. Collins, H. (2026) https://BioRender.com/ohe235n

Fibrillar collagens

Type I (Col1a1) and type III (Col3a1) fibrillar collagens are key ECM components and afford the heart structural integrity. These fibrillar collagens also play key roles in cell alignment and ensure equal stretch and contraction between sarcomeres in the heart(16). This collagen network ensures that myocytes function as a single contractile unit. The ratios of expression for these collagen transcripts can also be important for overall cardiac health and function. The Col1a1/Col3a1 ratio is an indicator of how the ventricular wall handles mechanical stress. An increase in the Col1a1/Col3a1 ratio has been associated with a decrease in ventricular compliance and an increase in myocardial stiffness(17, 18). In addition, recent studies suggest that how collagen is aligned and organized in the heart plays a key role in how the heart adapts to pathological stress(19); however, it is unclear how this may be impacted in response to physiological stressors. Collectively, this suggests that both collagen content, production, and organization are important for myocardial function.

Elastin, Fibronectin, and Integrins

Due to the predominant focus on the contribution of collagens to ECM structure, like other interstitial matrix components, the specific function of elastin within the myocardium is understudied. Elastin, together with collagen, has been shown to provide the myocardium with much of its stiffness and shear resistance. Studies of the decellularized myocardium support this relationship, in which cardiac tissue volume and structure were maintained following decellularization, suggesting that elastin and collagen support the myocardium even when no cells are present (20). Elastin has also been shown to play a role in overall myocardial contractility, as well as providing additional LV resistance and protection of the ventricular wall. In addition, elastin may play a key role in regulating collagen organization in the heart, as it does in the skin (21). The specific function of fibronectin within the myocardium is also largely underappreciated due to its lower levels in the uninjured heart(22); however, research suggests it plays roles in tissue repair and force generation. In addition, fibronectin polymerization appears necessary for ECM deposition in the context of cardiac injury(23). Fibronectin has also been shown to play a large part in cell growth, proliferation, and adhesion(22). Terracio et al. showed that myocytes from hypertrophied hearts exhibited increased attachment to fibronectin, suggesting that fibronectin may play a role in cell-collagen adhesion(24). Whether fibronectin plays a key role in responses to physiological stress remains unclear, because it does not appear to be involved in structural changes in the heart following exercise(25); however, studies have yet to examine how it may regulate pregnancy-induced cardiac remodeling. Cell-ECM interactions (including cell-collagen adhesion) and their mediators are essential for homeostasis and cardiovascular function in non-pregnant adult hearts(26). Integrins, the main mediators of cell-ECM interactions, bridge the ECM with the actin cytoskeleton, and play important roles in cardiac mechanotransduction, cell adhesion, cell migration, and ECM remodeling(27). While their specific role has yet to be defined, integrins have been implicated in multiple types of cardiovascular diseases(28), alluding to an important role in overall cardiac function.

Proteoglycans

Proteoglycans have also been understudied in the myocardium, but they play important roles within the cardiac ECM. Known proteoglycans include aggrecan, perlecan, syndecan, versican, decorin, and biglycan. Aggrecan has been shown to provide hydrodynamic properties to tissue, including regulating tissue swelling to withstand compression forces(29), and many proteoglycans, such as perlecan and syndecans are upregulated during hypertensive heart failure and cardiac remodeling(30, 31), suggesting that they play a key role in matrix remodeling in the context of injury. The proteoglycan, versican, alongside the glycosaminoglycan, hyaluronan, together afford the heart viscoelasticity, allowing the heart to deform during systole and recoil during diastole(32, 33). In addition, decorin and biglycan have reported roles in binding collagen fibers and regulating their organization(34). Although it is clear that proteoglycans have a significant modulatory role in ventricular biomechanics, they have been notoriously understudied in the context of physiological stress.

Matrix Regulating Components

As the interstitial matrix contributes heavily to cardiac structure and function, many of the changes that occur during ECM remodeling happen in the interstitial matrix(8). The cardiac ECM contains proteins that can degrade and regulate ECM components, such as adamalysins, which regulate cell adhesion and intracellular signaling(35); matrix metalloproteinases (MMPs), which play roles in cell migration, cell differentiation, pro-inflammatory processes, and cell apoptosis(36); and tissue inhibitors of metalloproteinases (TIMPs), which inhibit and regulate MMPs(35). Upregulation of MMPs is largely associated with an increase in ECM degradation and remodeling, while an upregulation of TIMPs results in the inhibition of these changes. MMPs modulate the overall composition of the interstitial matrix by degrading specific ECM proteins. MMPs target several ECM components during remodeling and act as collagenases (e.g., MMP 1, 8, and 13), gelatinases (e.g., MMP 2 and 9), stromelysins (e.g., MMP 3, 10, and 11), matrilysins (e.g., MMP 7 and 26), or are membrane type (e.g., MMP 14, 15, 16, 17, 24, and 25)(36). Mmp2, in particular, degrades Col1a1 and Col3a1, thereby promoting ECM remodeling(37) and due to its ability to degrade fibrillar collagen, this activation likely increases ventricular compliance and decreases stiffness. TIMPs inhibit this degradation, so an upregulation of TIMPs could lead to less ECM degradation and a buildup of these ECM proteins. These regulators are dynamic and respond to external stimuli, such as changes in cardiac function, cardiac load, or physiological stressors(38). A good example of physiological stress is the increase in cardiac load during pregnancy.

Cardiac Adaptations in the Maternal Heart

Throughout gestation, the maternal heart undergoes coordinated, reversible adaptations to support maternal-fetal circulatory demands. These functional and structural adaptations in the maternal heart begin shortly after conception, change over the course of a pregnancy, and are characteristic of adaptations seen across many mammalian species(39). In women, beginning at 5 weeks of gestation, cardiac output (CO) rapidly increases, due to increased stroke volume (SV), secondary to plasma volume expansion and a simultaneous reduction in systemic vascular resistance (SVR)(40, 41). An early decline in arterial pressure accompanies the widespread decrease in vascular resistance, which is also observed in mouse models within 3.5 days of conception(42). The expansion in maternal blood volume contributes to the development of pregnancy-induced cardiac hypertrophy. In rodents, these changes are typically observed in mid-pregnancy (i.e., days 8–10 of gestation), with documented increases in cardiac size, CO, and SV, and reductions in mean arterial pressure(5, 43, 44).

As pregnancy progresses into the second trimester, continued volume expansion and associated ventricular remodeling sustain elevated CO. Also in the second trimester, around 20–24 weeks, SVR reaches its nadir, marking the lowest point in blood pressure (BP) during gestation (40, 45). By the third trimester, HR peaks (~10–20 bpm above baseline), along with CO, plasma volume, and red blood cell mass. Late pregnancy also reveals the peak of eccentric cardiac hypertrophy, characterized by proportional chamber enlargement and wall thickening in response to volume overload, which occurs in humans in the third trimester (40, 41)and in mice at days 16–19 gestation(1, 2, 4, 5, 44, 46). Labor and birth represent physiological peaks in maternal hemodynamics, CO at this stage significantly exceeds pre-labor levels, propelled by contraction-induced autotransfusion, catecholamine release, and tachycardia(47). Following delivery, the various adaptations induced by pregnancy regress, with normalization of SVR and BP and gradual reversal of cardiac remodeling occurring over 2 weeks to 6 months postpartum in humans and within 3 weeks in mice(5, 40, 42). Although this rapid growth and reversion of the maternal heart likely require dynamic changes in the underlying ECM and likely impact the overall biomechanical properties of the heart, the specific underlying changes remain unclear.

Remodeling of the Cardiac ECM During Pregnancy

As discussed, the increased blood volume observed during pregnancy increases ventricular preload, resulting in the development of pregnancy-associated cardiac growth(4, 5, 43). The development of pregnancy-induced cardiac growth is likely associated with alterations in both ECM synthesis and degradation, which, in turn, affect the biomechanical properties of the heart and its ability to respond to stress; however, only a small number of rodent studies have examined this to date (see Table 1). One such study reported that deletion of Timp4, an ECM regulatory protein, was sufficient to cause significant changes in LV end-diastolic volume, end-systolic volume, SV, and ejection fraction(7). Ejection fraction was significantly increased at mid- and late-pregnancy timepoints, while SV was maintained. At late pregnancy, the Timp4^−/− mice also had higher collagen I protein expression and increased Mmp2 activity(7). These changes show that modulation of ECM components causes significant functional changes in the pregnant heart, but also changes in other ECM proteins and their functions.

Table 1.

Key Rodent Studies That Examine Cardiac ECM During a Healthy Pregnancy and Postpartum Period.

Study	PMID	Species, Strain, and Model Used	Age of Animals Assessed	Timepoints Examined	Key ECM Changes Documented
Limon-Miranda et al (2014)	PMID: 25147829	Rat; Sprague Dawley	3-month	Non-pregnant, diestrus Mid-pregnant (day 12) Late-pregnant (day 21) Postpartum (day 7)	1. Increased Col I and Col III mRNA during pregnancy. 2. Decreased Collagen I protein during pregnancy 3. Increased Collagen III protein during pregnancy 4. All changes in mRNA and protein are reversed by postpartum.
Virgen-Ortiz et al (2019)	PMID: 31126142	Rat; Sprague Dawley	3-month	Non-pregnant, diestrus Late-pregnant (day 21) Postpartum (day 7)	1. Increased perivascular and interstitial fibrosis in late pregnancy 2. MMP1, MMP2, and MMP9 decreased by late pregnancy 3. TIMP1 and TIMP4 upregulated at late pregnancy 4. All ECM changes reversed by postpartum
Virgen-Ortiz et al (2009)	PMID: 19565322	Rat; Sprague-Dawley	3-months	Non-pregnant, diestrus Late-pregnant (day 18–21) Postpartum day 7	1. Increase in heart-weight-to-body-weight ratio during pregnancy; reversed postpartum 2. Decreased passive tension in both left ventricle and right ventricle during late pregnancy 3. Decreased elastic modulus in both left ventricle and right ventricle during late pregnancy; reversed postpartum 4. Decreased hysteresis in both left ventricle and right ventricle during late pregnancy.
Sykora et al (2019)	PMID: 30908945	Rat; Wistar	3–4 months	Non-pregnant Pregnant non-hypoxic	1. No change in MMP2 expression between non-pregnant and pregnant groups
Fulghum et al (2022)	PMID: 35622533	Mouse; FVB/NJ	3-month	Non-pregnant, diestrus Mid-pregnant (day 8) Late-pregnant (day 16) Postpartum (day 7)	1. Absence of fibrosis during pregnancy and postpartum 2. Cardiac growth during late pregnancy and postpartum 3. Increased Col1a1, Col3a1, and Col5a1 at postpartum 4. Increased Lox at postpartum 5. Increased Postn and Fn1 at postpartum 6. Increased Lum and Dcn at postpartum
Umar et al (2012)	PMID: 22923507	Mouse; C57BL/6	3–4 months	Non-pregnant, diestrus Late pregnant (day 19–20) Postpartum day 7	1. Absence of fibrosis in late pregnancy 2. Cardiac growth at late pregnancy; reversed postpartum 3. Mmp2 mRNA downregulated at late pregnancy; reversed postpartum 4. Adam15 and Adam17 downregulated during late pregnancy; reversed postpartum
Parrot et al (2018)	PMID: 30541349	Mouse; C57BL/6	3-month	Non-pregnant, diestrus Pregnancy day 12 Pregnancy day 18/19 Postpartum day 1.5 Postpartum day 7	1. Col1a1 and Col3a1 increased during pregnancy and postpartum 2. Col8a1 increased postpartum only (day 1.5 and 7) 3. Timp1 increased in late pregnancy and postpartum 4. Timp2, Timp3, and Timp4 decreased in postpartum, with no change in pregnancy 5. Mmp3 increased late pregnancy and postpartum 6. Mmp13 increased at late pregnancy; decreased at postpartum 7. Mmp15 is unchanged at late pregnancy but decreased at postpartum day 7 8. Cardiac size increased during pregnancy and reduced in postpartum
Thurstin et al (2023)	PMID: 36459450	Mouse; C57BL/6; Global Timp4−/−	3-month	Virgin Pregnancy day 18 Postpartum day 2 Postpartum day 28	1. WT mice: cardiac size increased; increased Timp1 during postpartum day 2; increased Col3a1 and Col8a1 during postpartum day 2 2. KO mice: higher levels of Col1a1 and Col3a1; Collagen I further increased in late pregnancy and postpartum day 2; higher EF% to maintain SV. No detrimental changes in function.

The profile of the cardiac ECM changes significantly over the course of pregnancy (depicted in Figure 2), suggesting a relationship between ECM composition and changes in cardiac function and size during pregnancy (5, 6). Heart weight-to-tibia length ratio and cardiomyocyte cross-sectional area are significantly increased over the course of pregnancy(5). Specifically, late pregnancy and the early postpartum period are periods of heightened cardiac growth and are associated with significant changes in the expression of key ECM components, including several collagens and proteoglycans (5, 6); however, some conflicting findings have been reported between rodent studies. For example, Fulghum and colleagues reported that Col1a1 and Col3a1 were increased in the heart at late pregnancy and at postpartum day 7(5); however, Parrot and colleagues showed that Col1a1/Col3a1 was significantly reduced at late pregnancy (gestational days 18/19) but peaked at postpartum days 1.5 and 7, returning to baseline by postpartum day 28(6). Despite differences in Col1a1/Col3a1 between the two studies, neither study identified cardiac fibrosis in the maternal heart. Parrot et al. also did not observe differences in any proteoglycans; however, Fulghum et al. identified decreases in protein expression of lumican and decorin at postpartum day 7. Interestingly, although in many rodent models, cardiac remodeling is initiated at mid-pregnancy (i.e., between 8–12 days of pregnancy), the expression of ECM components identified to change at mid-pregnancy differs from those observed at both late pregnancy and early postpartum, highlighting the temporal nature of changes in key ECM components and ECM remodeling between pregnancy stages(5, 6). Virgen-Ortiz et al.(48) suggested that a significant decrease in passive tension, with decreased force generation from both right and left ventricular walls observed during late pregnancy, could be related to an increase in the Col3a1 content in the rat cardiac ECM during pregnancy, as Col3a1 is known to have elastic properties(49). In addition, to the upregulation of Col3a1, at postpartum, Fulghum et al. also reported increases in basement membrane collagens (Col4a1, Col4a2, and Col15a1) during this time, which correlated with an increase in cardiac hypertrophy(5).

Figure 2. Temporal Changes in Cardiac ECM Properties Throughout a Healthy Pregnancy.

The changes in the elastic modulus, collagen expression (i.e., collagens I and III), LV hypertrophy, and ECM remodeling shown reflect specific changes observed in non-pregnant hearts (i.e., at baseline) and throughout pregnancy up until early postpartum. This Figure was created in BioRender. Collins, H. (2026) https://BioRender.com/px02tu2

The ratios of Col1a1 and Col3a1 (50) are an important indicator of overall cardiac health and function. Both these collagen transcripts increase in expression over the course of pregnancy. When compared to virgin mice, both Col1a1 and Col3a1 expression were shown to increase during mid-pregnancy, late-pregnancy, and postpartum day 1.5(6). In a similar study, mRNA expression of Col1a1 and Col3a1 increased, but only Col3a1 protein expression increased in mid-pregnant and late-pregnant rats, with Col1a1 protein expression decreasing during these timepoints(49). This decrease in the Col1a1/Col3a1 protein ratio correlates with the decrease in passive tension shown by Virgen-Ortiz et al(48). Both Col1a1 and Col3a1 protein expression returned to pre-pregnancy levels in the postpartum period, which also correlates with the increase in passive tension seen by Virgen-Ortiz et al(48). This suggests an adaptive response by the maternal heart to the increase in blood volume by increasing cardiac compliance and reducing cardiac stiffness.

In addition to changes in the abundance of key collagen transcripts in the maternal heart, changes in the structure of the cardiac collagen network, such as a large decrease in tortuosity and an increase in collagen fiber length(51, 52) have been documented. Tortuosity can be described as ‘waves’ within the collagen fibers that ‘stretch out’ during the elongation of the tissues, but reappear when the force is no longer applied(53). This suggests that collagen tortuosity acts as a sort of recoil system within the tissue, and the amount of tortuosity in the collagen fibers has been shown to affect the overall extensibility of the heart tissue(54). Pierlot et al. showed an almost total loss of tortuosity within the mitral and aortic valves during pregnancy, and a 216% and 186% increase in fiber length in those valves, respectively(55). This decrease in tortuosity was associated with a decrease in heart valve leaflet extensibility by 11% in the aortic valve and 20% in the mitral valve(55). The decreases in extensibility and tortuosity were evident early in pregnancy, but only extensibility recovered to pre-pregnancy values by the late pregnancy timepoint. This means that tissue extensibility is recovered independently of tortuosity, but the actual mechanism is unknown(55). These decreases in extensibility and tortuosity were also accompanied by increased cardiac tissue area; as collagen is a large component of the heart, it is possible that the decrease in collagen tortuosity impacted this change in area. As the collagen fibers stretch out, they could possibly stretch the tissue around them, leading to an increase in tissue area and decreased extensibility. This phenomenon could explain part of the cardiac growth seen during pregnancy(55). While extensibility was measured, there are multiple other biomechanical properties that this could affect; this decrease in collagen tortuosity could possibly lead to decreased cardiac strain due to a decreased ability for a cardiac cycle to change myocardial dimensions because of the decrease in extensibility. These changes, however, were studied only in the mitral and aortic valves; a study of how tortuosity affects the extensibility of the other heart valves, as well as non-valvular changes, could provide a broader, more complete picture of how collagen tortuosity affects cardiac function.

Cardiac integrins and the cell-ECM interactions they mediate may also play a role in pregnancy(9); however, much of the research done in this area has focused on the function of integrins in fetal development(24). Even though integrins have been suggested to affect overall cardiac health(28), their involvement in the maternal cardiac adaptations has yet to be interrogated. With this, there is an overall lack of knowledge when it comes to integrins and cell-ECM interactions in the maternal heart, highlighting an important area for future investigation.

Pregnancy has also been shown to affect the biomechanical properties of the heart. In pregnancy, there is a reduction in passive tension and rigidity in ventricular tissue(48). Virgen-Ortiz et al. found that the elastic modulus decreased from 25.5 $\frac{mN}{m{m}^2}$ in the non-pregnant left ventricle to 14.8 $\frac{mN}{m{m}^2}$ in late pregnancy (18–21 days after gestation) but increased back to 25.4 $\frac{mN}{m{m}^2}$ 7 days postpartum in the pregnant rat(48). A decrease in passive tension of the ventricles was also observed that decreased in late pregnancy but returned to non-pregnant values in the postpartum period. This decrease in passive tension could correlate with the reduced extensibility and tortuosity observed during late pregnancy. Elastic hysteresis, a measurement of the difference between the energy used for mechanical loading and the energy recovered during mechanical unloading, is yet another biomechanical property affected by pregnancy. Virgen-Ortiz et al. also showed a decrease in hysteresis during pregnancy(48), meaning more energy is conserved between heart contractions. This suggests that the heart may be more efficient during pregnancy than in non-pregnant cases(48); however, hysteresis was shown not only to return to non-pregnant values postpartum, but to increase past the non-pregnant value. This shows that the heart loses more elastic energy postpartum than it does at the non-pregnant time point, suggesting that the heart may lose efficiency after pregnancy(48), which could lead to a period of cardiac vulnerability. Due to biomechanical feedback, increased hysteresis can induce cardiac arrhythmias and cardiac arrhythmia-induced cardiomyopathy(56), which could be a precipitating factor in arrhythmia burden during this time in some women. The mechanisms underlying changes in these properties have not been studied, highlighting the need for research that carefully assesses cardiac biomechanics over the course of pregnancy and the postpartum period. While there is a correlation between remodeling of the cardiac ECM profile during pregnancy and changes in these properties, how they might interact remains unknown.

Changes in matrix-regulating components contribute to cardiac ECM remodeling during pregnancy. Specifically, as mentioned, MMPs degrade the ECM and its components, whereas TIMPs inhibit the function of MMPs(36). The ratio of these proteins is very tightly controlled, and any imbalance could lead to abnormal regulation of ECM degradation and the perpetuation of disease(36, 57). In a mouse study, Parrott et al(6). found that cardiac Mmp3 was significantly upregulated during late pregnancy (gestational day 18/19) and the postpartum period, whereas cardiac Mmp13 was increased at late pregnancy then decreased in the early postpartum period (1.5 days postpartum) and cardiac Mmp15 was relatively unchanged during pregnancy but was downregulated in the late postpartum period (7 days). Timp1 levels were upregulated in late pregnancy (gestational day 18/19) and early postpartum (1.5 days postpartum), whereas Timp2, Timp3, and Timp4 levels were all unchanged during pregnancy but all reduced in expression in the postpartum period. These changes suggest that MMPs are remodeling the basement membrane (Mmp3) and interstitial collagen (Mmp13) during late pregnancy to allow for cardiomyocyte lengthening and maintenance of ventricular compliance. The changes in Timp1 in late pregnancy likely prevent excessive dilation of the heart under the stress of volume overload. The postpartum reductions in Timp2, 3, and 4 are likely the triggers of the regression of cardiac growth that remove the brakes on MMPs to permit degradation of type I and III collagens. Given that the ECM is regulated at the protein level, however, it remains unclear how many of these documented changes in transcript levels in the maternal heart correlate with protein level changes. Overall, the changes in the ratio of MMPs to TIMPs suggest that during a healthy pregnancy, highly controlled ECM remodeling is occurring to mediate structural adaptations (6). Due to this tight control of remodeling, any comorbidity that could contribute to adverse changes in these proteins or their ratios could precipitate pregnancy-related disease.

Contributions of Pregnancy-associated Hormonal Changes on Cardiac ECM Remodeling

Pregnancy is associated with several endocrine and hormonal changes that are necessary for successful implantation, maintenance of pregnancy, labor and delivery, and lactation. These hormonal changes include changes in estrogen (E2), progesterone, relaxin, and prolactin. Among the widely studied of these, E2, which peaks early in rodent pregnancy(4), has been reported to have an anti-fibrotic effect in the heart through the inhibition of TGF-β1 mediated fibroblast differentiation(58); however, it is important to note that this study was not performed in the context of pregnancy. Another key hormone known to directly affect the ECM is Relaxin, which is elevated in late pregnancy and begins to decline during the postpartum period(59). Relaxin, like E2, has been shown to be a key player in ECM dynamics(60), having an anti-fibrotic effect through its inhibition of TGF-β1–Smad2 signaling(61) and by mediating changes in the expression of several MMPs, including MMP2 and MMP9(62); however, these studies were conducted in non-cardiac tissues, with little known about changes in the maternal heart. Another key pregnancy hormone, progesterone, reaches its peak during late pregnancy in rodent models(4), however, despite its documented roles in shaping maternal cardiovascular metabolic changes and hypertrophy(3), its potential impact on the cardiac ECM is not understood. Likewise, despite increases from late pregnancy to the early postpartum period in rodent models of pregnancy, prolactin and its cleavage fragments have thus far only been documented to have vascular-endothelial effects during pregnancy(11), with little known about their potential direct and indirect effects on the cardiac ECM. Despite these documented changes in hormonal levels during pregnancy, their roles in regulating the ECM in other contexts, and the fact that cardiac fibroblasts express receptors for these hormones(63), limited studies have examined how these common pregnancy hormones directly regulate cardiac ECM remodeling in the context of a healthy pregnancy, thus additional studies are warranted to tease apart the impacts of these key hormones on the maternal cardiac ECM.

Remodeling of the Cardiac ECM in Response to Multiparity

Differences in parity shape long-term cardiovascular disease risk, with low parity (< 3 pregnancies) having beneficial consequences and high parity (< 5 pregnancies) increasing long-term cardiovascular disease risk(64, 65). Multiparity requires the female heart to possess a degree of plasticity to accommodate the multiple rounds of growth and reversion, likely impacting ECM dynamics and structure. While there has been little research on how multiparity might affect the cardiac ECM, Magaye et al.(66) recently reported increased mRNA expression of fibronectin in multiparous mice when compared to nulliparous mice, as well as increased expression of genes involved in fibronectin binding and an increase in cardiac fibrosis. These transcriptional changes in multiparous mice were associated with significant decreases in ejection fraction and significant increases in isovolumetric relaxation time, suggesting diastolic dysfunction(66). Despite this, they found no changes in Col1a1, Col3a1, Timp1, Timp2, Mmp9, or Mmp2 between the two groups. It is important to note; however, this is just one study, and further investigation into the effects of multiparity on the maternal heart are needed to better understand the mechanisms underlying these changes and how they might affect ventricular biomechanics.

ECM and Biomechanics of the Hypertrophic and Diseased Heart

While cardiac remodeling and adaptive hypertrophy occur in normal pregnancies, there are many pregnancy-associated cardiovascular complications that can negatively impact remodeling processes in the maternal heart, such as preeclampsia and peripartum cardiomyopathy (PPCM). The potential impact of these factors will now be discussed, and key ECM changes reported in these pathologies are shown in Figure 3.

Figure 3. Adverse Changes in Cardiac Function, ECM Remodeling, and ECM Proteins During Preeclampsia, Peripartum Cardiomyopathy, and Obese Pregnancies.

Abbreviations: PPCM, peripartum cardiomyopathy. Gene transcription changes shown in tissue inhibitor of metalloproteinase 1 (TIMP1), transforming growth factor beta 1 (TGFβ−1), matrix metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteinase 2 (TIMP2), matrix metalloproteinase 3 (MMP3), matrix metalloproteinase 9 (MMP9), tensin 3 (TNS3), and somatomedin B and thrombospondin type 1 domain-containing protein precursor (SBSPON). This Figure was created in BioRender. Collins, H. (2026) https://BioRender.com/fu7ba2n

Preeclampsia

Preeclampsia is characterized by an increase in blood pressure in a previously normotensive mother(67) in conjunction with proteinuria and/or thrombocytopenia, renal insufficiency, impaired liver function, or edema. Preeclampsia can present in either early or late pregnancy, with early presentation associated with increased severity of symptoms and disease progression(68). In preeclampsia, the female heart does not undergo the adaptive physiological eccentric hypertrophy seen in a healthy pregnancy; instead, it undergoes maladaptive concentric hypertrophy, along with left atrial enlargement, reduced end-diastolic volume, fibrosis, and subclinical diastolic dysfunction(9), which can result in unresolved remodeling. Of note, forty percent of formerly preeclamptic women were still shown to have left ventricular hypertrophy one and two years postpartum(69). This maladaptive remodeling and persistent hypertension can lead to more severe cardiac problems in the future; 23% of formerly preeclamptic women presented with heart failure, and 78% of those women with heart failure presented with heart failure with preserved ejection fraction years after pregnancy(70). This heart failure is more likely to be asymptomatic and therefore does not spur patients to seek medical care until it is likely too late, increasing mortality risk for female patients with this disease(71).

Not surprisingly, components of the cardiac ECM are affected by preeclampsia and resultant concentric hypertrophy of the heart. Tgfb1, a pro-inflammatory ECM protein, is upregulated in preeclampsia(69). Tgfb1 has been shown to reduce collagen degradation and increase collagen synthesis, resulting in cardiac fibrosis and an imbalance in the Col1a1/Col3a1 ratio(72). Fibronectin, which is immunomodulatory, is significantly upregulated in preeclamptic women compared to normotensive pregnant controls, which may also promote collagen deposition (69). Pro-inflammatory proteins play a key role in fibroblast activation and increased ECM deposition; therefore, an increase in these proteins could lead to adverse fibroblast activation and may contribute to the concentric hypertrophy and fibrosis seen with preeclampsia(23).

MMPs and TIMPs are upregulated during pregnancy and downregulated during the postpartum period, suggesting that MMP-mediated ECM degradation is controlled and remains constant throughout pregnancy. This is not the case in a preeclamptic pregnancy. Serum Mmp2, Timp1, and Timp2 were reported to be significantly higher in preeclamptic pregnancies than in either nonpregnant women or women with uncomplicated pregnancies(73). Serum protein levels have been shown to correspond to cardiac changes, and serum Timp1 has been shown to correlate with worsening cardiac function(51). Even though both TIMPs and MMPs appear to be upregulated during preeclamptic pregnancies, as in healthy pregnancies, it was also demonstrated that there was an imbalance in the Mmp2/Timp1 ratio in preeclamptic women(74). While the authors did not interrogate protein expression directly, this ratio imbalance likely affects cardiac function and remodeling (75). This demonstrates inhibition of ECM degradation, consistent with adverse cardiac ECM remodeling during a pre-eclamptic pregnancy, and could explain part of the adverse remodeling and fibrosis associated with a pre-eclamptic pregnancy(73). Elevated Timp1 levels have also been shown in pathological left ventricular hypertrophy and suggest that an upregulation of Timp1 could be a sign of cardiac fibrosis, which would explain many of the symptoms seen in preeclampsia and other related conditions, such as PPCM and HFpEF(69). The connection between preeclampsia, ECM regulatory proteins, and cardiac fibrosis has not been well established and needs further study before any definitive conclusions can be drawn.

Peripartum Cardiomyopathy

Preeclampsia is not the only pregnancy-associated cardiovascular disease that impacts the ECM. PPCM is highly correlated with preeclampsia(76) and results in an idiopathic systolic dysfunction during late pregnancy into the postpartum period that can progress to overt heart failure(11), and is associated with increased cardiac fibrosis(10, 77). Li et al., showed that somatomedin B and thrombospondin type 1 domain-containing protein precursor (SBSPON), a predicted extracellular structural protein that contributes to tissue remodeling, and tensin 3 (TNS3), a protein involved in the control of ECM remodeling(78), were both uniquely downregulated in cardiac tissue from women with PPCM. This reduced expression suggests that there is reduced control of ventricular remodeling in PPCM hearts(78); however, despite this, and increased fibrotic burden often observed in the PPCM heart, little is known about the mechanisms that drive this pathology. Although rodent models of PPCM exhibiting increased cardiac fibrosis(10, 77), which has recently been associated with immune changes(79), no further examination of matrix-related changes have been performed and thus warrant further investigation.

Obesity and Gestational Diabetes (GDM)

Given the increasing rates of obesity and metabolic syndrome amongst women of childbearing age(80), it is not surprising that obesity has a significant impact on the remodeling of the maternal heart. For example, pregnant mice that were fed a high-fat diet four weeks before and throughout pregnancy, not only had significant increases in body mass, but their hearts showed increased expression of Mmp3, Mmp9, Col1a1, and Col1a3 during the postpartum period, as well as a reduced Timp1/Mmp3 and Timp1/Mmp9 ratio, which was associated with increased LV mass(81). Of note, this pattern of ECM gene expression remained altered in obese mice up to ten weeks postpartum (81). Obesity is also a risk factor for gestational diabetes mellitus (GDM), which comes with its own set of functional complications. Women with GDM have significantly increased heart mass, LV wall thickness, and LV mass, as well as significantly decreased end diastolic volume and global longitudinal strain, and significantly increased systolic and diastolic blood pressures(82). There appears to be a lack of studies examining specific ECM changes in the pregnant heart in GDM, yet it is clear that both obesity and GDM are significant risk factors for maladaptive functional and biomechanical changes in the maternal heart.

Advanced Maternal Age

Advanced maternal age is rapidly becoming a prominent risk factor for maternal cardiovascular disease(83), with women choosing to have children later in life. Aging, although a natural physiological process, is associated with several changes in the heart that can precipitate cardiovascular disease. Several studies have suggested that aged rodent (i.e., 18–24 months) hearts exhibit increased inflammatory macrophage infiltration, which contributes to fibroblast activation and myofibroblast conversion, but also increased interstitial and perivascular fibrosis(84). In addition, aged rodent studies have reported heightened ECM degradation through increases in the expression of MMPs, including MMP9, changes in integrin expression, and collagen crosslinking (85–88). Collectively, these changes in the aged heart create an environment characterized by heightened diastolic dysfunction and reduced ventricular compliance. Although these changes are known to occur with aging in mice, few studies have examined these changes in the context of pregnancy. Of the rodent studies that have examined advanced maternal age (58, 64), although adverse structural and functional changes were found, little mechanistic interrogation focused on ECM remodeling was performed, highlighting the need for additional work in this area.

These changes suggest that ECM remodeling is significantly affected in pregnancies burdened by cardiovascular pathology. As discussed earlier, these changes in ECM remodeling are associated with changes in cardiac tissue extensibility and rigidity, contractility, and overall cardiac hypertrophy. These changes in remodeling affect whether and when the heart returns to its pre-pregnancy state; any deviation from ‘normal’ remodeling can impact how quickly the heart recovers, if it recovers at all. These pathological changes in ECM remodeling may increase the risk of certain heart pathologies in the future. For example, unresolved ventricular remodeling and hypertension observed following preeclampsia likely play a role in the observed increased risk of HFpEF development later in life(89); however, additional studies into the mechanisms behind these changes are required to fully understand how the presence of these cardiovascular changes during pregnancy may precipitate increased risk of cardiovascular pathologies in the future.

Conclusions

Remodeling of the maternal heart involves coordinated changes in various components, including the ECM. Among the changes in ECM-related proteins that occur during physiological cardiac remodeling during pregnancy, the most conspicuous of these changes are those related to changes in collagen expression (i.e., changes in Col1a1/Col3a1 ratios) and changes in ECM regulators (MMPs and TIMPs). These changes suggest significant ECM remodeling in the maternal heart, but an in-depth interrogation of the contributing mechanisms has yet to be performed. It is important that the field places greater focus on in-depth analyses of these changes in the context of pregnancy, such as single-cell-level analyses, which could provide a more thorough understanding of how the cardiac ECM changes during pregnancy and how those changes could become maladaptive and contribute to pregnancy-related cardiovascular pathologies. While analyses conducted thus far have contributed to our overall understanding of maternal cardiovascular remodeling, it is important to understand how and why each of these ECM components changes, and what physiological impact they have on maternal cardiac plasticity and ventricular biomechanics.

While both changes in maternal cardiac ECM-related protein expression and in biomechanics during pregnancy have been shown in a small number of studies (see Table 1), the direct link between the two still needs to be interrogated. Although correlations have been suggested, such as increases in collagen synthesis leading to increased cardiac stiffness, this has yet to be mechanistically studied in-depth in the context of pregnancy. In addition, examining differences in the ECM in pathological pregnancies (e.g, preeclampsia and PPCM) could provide novel insights into the mechanisms driving these pathologies and possibly explain some of the maladaptive changes observed. Studying the biomechanical properties of the ECM itself could lead to novel insights into how ECM deformation rates, hysteresis, and elastic moduli or fibroblast contractility interact and contribute to overall cardiac function and biomechanical properties over the course of pregnancy and the postpartum period. In addition, this knowledge will be essential for understanding adverse cardiac remodeling in the context of pathological pregnancies. In summary, the largest knowledge gaps to be addressed in the context of maternal cardiovascular remodeling include:

• Identification of underlying pathways contributing to ECM remodeling during pregnancy and the resultant consequences on ventricular biomechanics.

• Examination of how the cardiac ECM is modulated by maternal cardiovascular diseases and relevant comorbidities.

• How pregnancy-related factors, such as parity and advanced maternal age, and environmental factors, such as diet, may impact ECM remodeling and biomechanics.

• How the circulating milieu (i.e., circulating hormones, growth factors, immune cells, and metabolites) directly or indirectly modulates components and cells of the ECM.

• Identification of physiological “tipping points” that reduce maternal cardiac plasticity and precipitate perturbations

• Identification of biomarkers that can be used to detect early stages of disease or be targeted and exploited to reduce adverse matrix remodeling during maternal cardiovascular disease.

Overall, very little is known about how the female heart remodels during periods of stress(90), especially during pregnancy and the postpartum period, which is an area in which reduced emphasis has been historically placed. This has resulted in a reduced level of knowledge regarding how the ECM remodels during pregnancy and the postpartum period. Most of the published studies focus on maternal cardiac remodeling in the context of cardiomyocyte hypertrophy, but evidence suggests that a large contributor to this remodeling may lie within the ever-changing expression and regulation of ECM components. Thus, it is important to look at every aspect that may be affected by or contribute to pregnancy-induced cardiac remodeling to gain a better understanding of the female heart, so that we understand how it changes and how to better protect it.